You searched for subject:(Medical Immunology).
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McMaster University
1.
Hanson, Stephen J.
TARGETING THE TUMOUR ASSOCIATED ANTIGENS PLAC1 AND GP100 WITH ONCOLYTIC CANCER VACCINES.
Degree: 2013, McMaster University
URL: http://hdl.handle.net/11375/13490 
► In spite of the tremendous body of cancer research, cancer remains a significant health issue requiring development of better therapeutics. The elucidation of the…
(more)
▼ In spite of the tremendous body of cancer research, cancer remains a significant health issue requiring development of better therapeutics. The elucidation of the relationship between cancer and the immune system and the identification of tumour associated antigens together suggest that novel therapeutics using the immune system to target cancer is a promising avenue of research. Since immunological tolerance is a barrier to generating immune responses to self antigen, strategies to circumvent tolerance need to be investigated to target given antigens. Plac1 is a novel tumour associated antigen with expression restricted to placenta, testis and many tumour cells. Initial reports concerning the expression, immunogenicity and potential tumourigenic function of Plac1 suggest that it would be an ideal tumour antigen. Initial experiments in mice indicated that generating an immune response against the murine Plac1 would be difficult and the subsequent work sought to employ strategies to facilitate anti murine Plac1 immune responses and anti tumour efficacy in Plac1 expressing tumours. Another more studied tumour associated antigen is gp100. Unlike Plac1, immune responses against the murine gp100 can be generated through vaccination. These responses are unable to demonstrate any anti tumour activity in gp100 expressing cells. The bulk of the gp100 studies described here sought to modify the immune:tumour interaction such that the anti tumour activity of the anti gp100 responses could be improved. While the specific barriers to Plac1 vaccination and efficacy and gp100 vaccination and efficacy are different, they have in common that they represent likely issues in using therapeutic cancer vaccines clinically. In both cases investigating how these barriers can be overcome is important and relevant to the understanding of these barriers to success when they appear in the clinic.
Advisors/Committee Members: Lichty, Brian, Medical Sciences (Molecular Virology and Immunology Program).
Subjects/Keywords: Medical Immunology; Medical Immunology
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APA (6th Edition):
Hanson, S. J. (2013). TARGETING THE TUMOUR ASSOCIATED ANTIGENS PLAC1 AND GP100 WITH ONCOLYTIC CANCER VACCINES. (Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/13490
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Hanson, Stephen J. “TARGETING THE TUMOUR ASSOCIATED ANTIGENS PLAC1 AND GP100 WITH ONCOLYTIC CANCER VACCINES.” 2013. Thesis, McMaster University. Accessed April 10, 2021.
http://hdl.handle.net/11375/13490.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hanson, Stephen J. “TARGETING THE TUMOUR ASSOCIATED ANTIGENS PLAC1 AND GP100 WITH ONCOLYTIC CANCER VACCINES.” 2013. Web. 10 Apr 2021.
Vancouver:
Hanson SJ. TARGETING THE TUMOUR ASSOCIATED ANTIGENS PLAC1 AND GP100 WITH ONCOLYTIC CANCER VACCINES. [Internet] [Thesis]. McMaster University; 2013. [cited 2021 Apr 10].
Available from: http://hdl.handle.net/11375/13490.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hanson SJ. TARGETING THE TUMOUR ASSOCIATED ANTIGENS PLAC1 AND GP100 WITH ONCOLYTIC CANCER VACCINES. [Thesis]. McMaster University; 2013. Available from: http://hdl.handle.net/11375/13490
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Arizona
2.
Buckley, Maverick J.
Matrix Matters: Biomarker Potentials of Phagocytes, Exosomes, and Cytokines
.
Degree: 2019, University of Arizona
URL: http://hdl.handle.net/10150/632209
► Overview: The Applied Biosciences Professional Science Masters (ABS-PSM) program at the University of Arizona prepares students in the fields of biological science to enter areas…
(more)
▼ Overview: The Applied Biosciences Professional Science Masters (ABS-PSM) program at the University of Arizona prepares students in the fields of biological science to enter areas of business and scientific competition. This interdisciplinary course of study involves the completion of an internship wherein students demonstrate scientific inquiry in the context of the goals and economic pursuits of the hosting agency. Students are required to convey how their projects contribute to the ambitions of the company or academic institution as well as to the larger scientific field. In this report, two internship projects completed to fulfill this requirement for the ABS-PSM degree will be described.
Biomedical research and diagnostics rely heavily on the use of biomarkers for drug discovery and disease management. Biomarkers are “characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions,” as defined by the National Institutes of Health Biomarkers Definitions Working Group (2001). Drug development and many facets of clinical diagnostics involve the measurement of a combination of biomarkers to evaluate the status of disease in an individual or their physiological changes following some treatment. In contrast to symptoms, biomarkers are not perceived by the patient but rather are observed from outside the patient (Strimbu & Tavel, 2010). The most well-studied biomarkers, such as troponin for the assessment of cardiac injury (Babuin & Jaffe, 2005), are applied regularly in predicting the incidence or outcome of a disease. This use of biomarkers as clinically meaningful surrogate endpoints is entirely justifiable, but only when such a characteristic has extensively and repeatedly proven predictive of outcome (Strimbu & Tavel, 2010). Additionally, the most logical biomarkers are those directly involved in the pathophysiology of a certain pathway, enabling more accurate interpretations of an individual’s disease status to be made.
The evaluation of a biomarker’s potential is challenged by the way in which it is measured. Biological samples are wide in variety, and, aside from ensuring the marker is present in the medium at all, determining what sample type is most compatible with existing instruments and what is most associated with a disease or anatomic site is a complex task. Cardiac troponin, for example, is measured in a peripheral blood sample to assess heart damage. The correlation of this enzyme’s concentration in the blood with heart muscle damage makes it a valuable disease indicator because the enzyme is produced in cardiac tissue and immediately released into the circulation (Antman et al., 1996). Neurodegenerative disease markers are markedly complicated because their presence in conventional fluid samples may not be accurately representative of concentrations in the brain. MSDx, Inc. (Tucson, AZ), a company that develops diagnostic solutions for neurodegenerative diseases, has identified…
Advisors/Committee Members: Ahmad, Nafees (advisor), Ahmad, Nafees (committeemember), Wesselhoft, Marie (committeemember), Nayak, Ramesh (committeemember), Wertheimer, Anne (committeemember), Lybarger, Lonnie (committeemember).
Subjects/Keywords: medical microbiology & immunology
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APA (6th Edition):
Buckley, M. J. (2019). Matrix Matters: Biomarker Potentials of Phagocytes, Exosomes, and Cytokines
. (Masters Thesis). University of Arizona. Retrieved from http://hdl.handle.net/10150/632209
Chicago Manual of Style (16th Edition):
Buckley, Maverick J. “Matrix Matters: Biomarker Potentials of Phagocytes, Exosomes, and Cytokines
.” 2019. Masters Thesis, University of Arizona. Accessed April 10, 2021.
http://hdl.handle.net/10150/632209.
MLA Handbook (7th Edition):
Buckley, Maverick J. “Matrix Matters: Biomarker Potentials of Phagocytes, Exosomes, and Cytokines
.” 2019. Web. 10 Apr 2021.
Vancouver:
Buckley MJ. Matrix Matters: Biomarker Potentials of Phagocytes, Exosomes, and Cytokines
. [Internet] [Masters thesis]. University of Arizona; 2019. [cited 2021 Apr 10].
Available from: http://hdl.handle.net/10150/632209.
Council of Science Editors:
Buckley MJ. Matrix Matters: Biomarker Potentials of Phagocytes, Exosomes, and Cytokines
. [Masters Thesis]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/632209
University of Louisville
3.
Zirnheld, Arin Lee.
The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.
Degree: PhD, 2013, University of Louisville
URL: 10.18297/etd/2266
;
https://ir.library.louisville.edu/etd/2266
► We identified and characterized a novel defect in β-catenin expression in bone marrow derived dendritic cells (BMDC) from NOD mice, a model for human…
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▼ We identified and characterized a novel defect in β-catenin expression in bone marrow derived dendritic cells (BMDC) from NOD mice, a model for human Type I diabetes. This protein is expressed at high levels throughout the lifespan of the mouse and correlates with increased pro-inflammatory cytokine production by the BMDC and IFNγ induction by T cells cocultured with the BMDC. These defects, including a similar pattern of pro-inflammatory cytokine production, are also observed in human monocytederived DC from diabetic patients. After exploring several potential mechanisms involved in the accumulation of β-catenin in NOD BMDC, we found that β-catenin is phosphorylated at higher levels in NOD BMDC at two residues associated with increased stabilization of this protein. Upon inhibition of the two kinases responsible for these phosphorylations, Akt and PKA, β-catenin expression is reduced. Therefore, β-catenin accumulates in NOD BMDC through an Akt and PKA-mediated mechanism. We also explored mechanisms by which β-catenin influences pro-inflammatory cytokine production and found that inhibition of β-catenin leads to decreased activation of the transcription factor NFκB, suggesting that pro-inflammatory cytokine production is increased in NOD BMDC through an NFκB-dependent mechanism. Finally, we performed several
in vivo experiments aimed at inhibiting β-catenin activity or reducing β-catenin expression to reduce disease incidence and/or increase survival. Treatment of NOD mice with quercetin, a β-catenin inhibitor, led to reduced disease incidence and a decreased inflammatory environment. Transfer of β-catenin siRNA-treated BMDC into NOD mice also reduced disease incidence. These studies reveal that β-catenin plays a role in the inflammation leading to diabetes development.
Advisors/Committee Members: Alard, Pascale, Kosiewicz, Michele, Kosiewicz, Michele, Warner, Dennis, Mitchell, Thomas, Venkatakrishna, Jala.
Subjects/Keywords: Medical Immunology; Medical Microbiology
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APA (6th Edition):
Zirnheld, A. L. (2013). The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development. (Doctoral Dissertation). University of Louisville. Retrieved from 10.18297/etd/2266 ; https://ir.library.louisville.edu/etd/2266
Chicago Manual of Style (16th Edition):
Zirnheld, Arin Lee. “The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.” 2013. Doctoral Dissertation, University of Louisville. Accessed April 10, 2021.
10.18297/etd/2266 ; https://ir.library.louisville.edu/etd/2266.
MLA Handbook (7th Edition):
Zirnheld, Arin Lee. “The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.” 2013. Web. 10 Apr 2021.
Vancouver:
Zirnheld AL. The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development. [Internet] [Doctoral dissertation]. University of Louisville; 2013. [cited 2021 Apr 10].
Available from: 10.18297/etd/2266 ; https://ir.library.louisville.edu/etd/2266.
Council of Science Editors:
Zirnheld AL. The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development. [Doctoral Dissertation]. University of Louisville; 2013. Available from: 10.18297/etd/2266 ; https://ir.library.louisville.edu/etd/2266
McMaster University
4.
Marcinko, Josip.
EVOLUTION OF ALLERGEN RESPONSIVENESS DURING DEVELOPMENT.
Degree: MSMS, 2011, McMaster University
URL: http://hdl.handle.net/11375/10971
► Background: Early infancy is a critical period during which the interplay between host and environmental factors influences susceptibility to allergic sensitization, a process that…
(more)
▼ Background: Early infancy is a critical period during which the interplay between host and environmental factors influences susceptibility to allergic sensitization, a process that can also be construed as a failure to induce tolerance. Indeed, allergic asthma emerges, in most instances, in early childhood although the specific intervals of protection or susceptibility remain to be elucidated. We found that exposure to a concentration of allergen, house dust mite (HDM), that normally induces robust airway inflammation in adult mice elicits negligible immune-inflammatory responses in infant mice. Methods: We investigated immune-inflammatory responses in mice exposed to 25 μg of HDM intranasally for 10 consecutive days at different points in development (3, 4, 5 and 7 weeks of age). We delineated the immune cell profile in the lungs of naïve mice from birth to adulthood, focusing on markers of immune maturation and immunosuppression. Moreover, we studied the impact of T-regulatory cell (Treg) depletion with the use of α-CD25 antibodies administered intraperitoneally one day prior to the start of HDM exposures, and then again on day 6 of the above protocol. Results: Our data show that there is a progressive acquisition of immune-inflammatory responsiveness to HDM in BALB/c mice as exposures are initiated later in development, evidenced by total cell number and eosinophilia in the BAL and serum HDM-specific IgG
1 levels. Additionally, there is an immunological shift that occurs in the infant lung during development in that the early immunosuppressive environment, defined by T-regulatory cells and immunosuppressive alveolar macrophages, subsides as the capacity to respond to ensuing immune challenges, defined by natural killer (NK) cell, dendritic cell (DC) and alveolar macrophage (AM) maturation, increases. Specifically, in regards to the immunosuppressive lung environment during infancy, we identified higher baseline levels of CD25
+Foxp3
+CD101
+ and CD25
+Foxp3
high Tregs, i.e. those with more potent suppressive ability. These populations also expand following HDM exposure in both adult and infant mice. Interestingly, 2 week-old infant mice depleted of Tregs or exposed to a very high dose of HDM (125 μg) overcome the natural immunosuppressive environment resulting in the acquisition of HDM responsiveness, as manifested by robust Th2 immune-inflammatory responses, comparable to that observed in 8 week-old adult mice. Conclusion/Implications: Together, our data suggest that the hyporesponsiveness to HDM very early in life may be explained by two connected events: a) the inherent immunosuppressive environment in the lung, and b) the immaturity of the machinery for effective immune responses. Furthermore, we demonstrate that a disruption in the homeostatic immune balance in infancy, Treg depletion in this case, may lead to the imprinting of aberrant immune-inflammatory…
Advisors/Committee Members: Jordana, Manel, Dawn Bowdish, Martin Stampfli, Dawn Bowdish, Martin Stampfli, Health Sciences.
Subjects/Keywords: allergic asthma; immunology; development; Medical Immunology; Medical Immunology
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APA (6th Edition):
Marcinko, J. (2011). EVOLUTION OF ALLERGEN RESPONSIVENESS DURING DEVELOPMENT. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/10971
Chicago Manual of Style (16th Edition):
Marcinko, Josip. “EVOLUTION OF ALLERGEN RESPONSIVENESS DURING DEVELOPMENT.” 2011. Masters Thesis, McMaster University. Accessed April 10, 2021.
http://hdl.handle.net/11375/10971.
MLA Handbook (7th Edition):
Marcinko, Josip. “EVOLUTION OF ALLERGEN RESPONSIVENESS DURING DEVELOPMENT.” 2011. Web. 10 Apr 2021.
Vancouver:
Marcinko J. EVOLUTION OF ALLERGEN RESPONSIVENESS DURING DEVELOPMENT. [Internet] [Masters thesis]. McMaster University; 2011. [cited 2021 Apr 10].
Available from: http://hdl.handle.net/11375/10971.
Council of Science Editors:
Marcinko J. EVOLUTION OF ALLERGEN RESPONSIVENESS DURING DEVELOPMENT. [Masters Thesis]. McMaster University; 2011. Available from: http://hdl.handle.net/11375/10971
Johannes Gutenberg Universität Mainz
5.
Reuter, Sebastian.
Die Rolle der Mastzelle bei der Entstehung einer allergischen Atemwegserkrankung.
Degree: 2009, Johannes Gutenberg Universität Mainz
URL: http://ubm.opus.hbz-nrw.de/volltexte/2010/2165/
► In der vorliegenden Arbeit wurde die Rolle der Mastzelle und deren Mediatoren für die Entstehung einer allergischen Atemwegsentzündung untersucht. Anhand von zwei mastzelldefizienten Mausstämmen (C57BL/6-KitWsh/Wsh…
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▼ In der vorliegenden Arbeit wurde die Rolle der Mastzelle und deren Mediatoren für die Entstehung einer allergischen Atemwegsentzündung untersucht. Anhand von zwei mastzelldefizienten Mausstämmen (C57BL/6-KitWsh/Wsh und WBB6FI-KitW/Wv), konnte gezeigt werden, dass Mastzellen an der Entstehung einer allergischen Entzündung und Atemwegsüberempfindlichkeit beteiligt sind. Durch die Rekonstitution von mastzelldefizienten Tieren mit aus Knochenmark gewonnenen Mastzellen (BMMC) von Wildtyp-Spendern konnte die wichtige Funktion der Mastzelle in diesem Model bestätigt werden. Überdies konnte durch die Rekonstitution mit TNF-defizienten BMMC eine wichtige Rolle für diesen mastzellproduzierten Mediator im allergischen Modell demonstriert werden. Weiterhin konnte die Arbeit zeigen, dass Mastzellen wichtig für die Migration von antigenbeladenen Dendritischen Zellen aus der Lunge in die regionalen Lymphknoten sind. Dieses stellt einen wichtigen Schritt für die Ausbildung einer lokalen allergischen Antwort dar. Im Gegensatz dazu war die Entstehung einer allergischen Atemwegserkrankung nach Transfer von in vitro generierten DC und Allergenprovokation nicht mastzellabhängig. Diese Ergebnisse zeigen, dass es auf die Wahl des Sensibilisierungs- und Provokationsmodels ankommt, um mastzellspezifische Effekte zu demonstrieren. Die vorliegende Arbeit zeigt die wichtige Rolle der Mastzelle und von mastzellproduziertem TNF bei der Ausbildung einer allergischen Entzündung der Atemwege. Die Mastzelle und deren Mediatoren stellen somit mögliche Ziele für die therapeutische Behandlung der allergischen Entzündung der Atemwege dar.
In the present work the role of mast cells and their mediators in the induction of an allergic airway disease was assessed. Two different mast cell-deficient mouse strains were used (C57BL/6-KitWsh/Wsh and WBB6FI-KitW/Wv). It could be demonstrated, that following sensitization and allergen challenge mast cells are necessary for the development of airway inflammation and airway hyperreactivity. Reconstitution of mast cell-deficient animals with bone marrow derived mast cells (BMMC) from wild type donors confirmed the important role of mast cells in this model. Moreover, reconstitution with BMMC generated from TNF-deficient animals revealed an important function of this cytokine in the mast cell dependent allergic airway model. Furthermore the work demonstrates that mast cells are important for an enhanced migration of antigen-laden dendritic cells from the lung to the draining lymph node, which is an important step in the development of a local allergic response. However, sensitization with in vitro antigen-laden dendritic cells was not dependent on mast cells. These data demonstrate that the choice of the allergen exposure protocol is important to reveal mast cell specific effects in the induction of immune responses. This doctoral thesis demonstrates the important role of mast cells and mast cell produced TNF in the development of an allergic airway inflammation. Mast cells and their produced mediators represent…
Subjects/Keywords: Immunologie; Immunology; Medical sciences Medicine
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APA (6th Edition):
Reuter, S. (2009). Die Rolle der Mastzelle bei der Entstehung einer allergischen Atemwegserkrankung. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2010/2165/
Chicago Manual of Style (16th Edition):
Reuter, Sebastian. “Die Rolle der Mastzelle bei der Entstehung einer allergischen Atemwegserkrankung.” 2009. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed April 10, 2021.
http://ubm.opus.hbz-nrw.de/volltexte/2010/2165/.
MLA Handbook (7th Edition):
Reuter, Sebastian. “Die Rolle der Mastzelle bei der Entstehung einer allergischen Atemwegserkrankung.” 2009. Web. 10 Apr 2021.
Vancouver:
Reuter S. Die Rolle der Mastzelle bei der Entstehung einer allergischen Atemwegserkrankung. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2009. [cited 2021 Apr 10].
Available from: http://ubm.opus.hbz-nrw.de/volltexte/2010/2165/.
Council of Science Editors:
Reuter S. Die Rolle der Mastzelle bei der Entstehung einer allergischen Atemwegserkrankung. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2009. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2010/2165/
Florida State University
6.
Keshavarz, Behnam.
Immunodetection of Allergens from Mullet (Mugil Cephalus) and Salmon (Salmo Salar).
Degree: PhD, Nutrition, Food, and Exercise Science, 2017, Florida State University
URL: http://purl.flvc.org/fsu/fd/FSU_2017SP_Keshavarz_fsu_0071E_13780
;
► The presence of misbranding and undeclared allergenic residues was the number one cause of food recalls in the United States, between 2012 to 2016. In…
(more)
▼ The presence of misbranding and undeclared allergenic residues was the number one cause of food recalls in the United States, between 2012 to 2016. In this study, parvalbumin was used as a model to study the matrix effect on thermostability of this protein. In general, parvalbumin is thermostable; however, its thermostability varies among different fish species. Identification of new fish allergens is also another important factor for the development of immunoassays to determine allergen-specific IgE antibodies. The specific objectives of this study were to: 1) study the matrix effect on thermostability of parvalbumin from mullet and salmon using three sample models, and 2) identify new potential fish allergen(s) and evaluate the in vitro pepsin digestion stability of suspect allergen(s). To fulfill objective 1, three sample systems were studied: soluble protein extracts from hot smoked samples, protein extracts (PE), and purified parvalbumin (PP). The PE and PP samples were heated for 0, 2, 5 and 8 min at 100 °C, respectively. BCA assay, SDS-PAGE, indirect non-competitive ELISA (inELISA), and Western blot (WB) were used to study the relative protein solubility (RPS), molecular integrity, relative immunoreactivity (RI), and antigenicity of parvalbumin in PE and PP samples., respectively. The amino acid (AA) sequence of mullet parvalbumin was determined using LC-MS/MS. Overall, RPS of PE samples heated for 8 min, compared with unheated samples, were significantly decreased (P < 0.05) in both species; however, no significant decreases (P < 0.05) were observed in RPS of PP samples. From SDS-PAGE, parvalbumin color intensity in PP model did not change over the heating time. Whereas, it was decreased in the salmon smoked and heated PE. From ELISA, in mullet PE, RI of heated samples did not significantly change (P > 0.05). However, RI of salmon PE significantly decreased (P < 0.05) as a function of heating time. The RI of mullet PP was not significantly different over the heating time (P > 0.05), while RI in 8-min heated salmon PP was significantly increased. From the WB, antigenicity of parvalbumin was decreased in the salmon heated PE samples. No changes were observed in the parvalbumin antigenicity in hot smoked mullet samples as well as mullet PE and PP samples. Amino acid sequence comparison also revealed a greater number of cysteine amino acid in salmon parvalbumin compared with mullet parvalbumin. This indicates that salmon parvalbumin is more engaged in heat-induced protein interactions and aggregation. In summary, PP was thermostable in both species. Mainly due to heat-induced protein interactions, the matrix effect on the thermostability of salmon parvalbumin was greater than that of mullet parvalbumin. This study demonstrates that the sample matrix effect can significantly affect in vitro studies related to food allergenic proteins. To fulfill objective 2, identification of new potential allergens in crude proteins extracts of heated mullet and salmon mullet and salmon was performed using seven fish allergic…
Advisors/Committee Members: Peggy Hsieh (professor co-directing dissertation), Qinchun Rao (professor co-directing dissertation), P. Bryant Chase (university representative), Bahram H. Arjmandi (committee member), Jeong-Su Kim (committee member), Shridhar K. Sathe (committee member).
Subjects/Keywords: Food; Medical sciences; Immunology
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APA ·
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APA (6th Edition):
Keshavarz, B. (2017). Immunodetection of Allergens from Mullet (Mugil Cephalus) and Salmon (Salmo Salar). (Doctoral Dissertation). Florida State University. Retrieved from http://purl.flvc.org/fsu/fd/FSU_2017SP_Keshavarz_fsu_0071E_13780 ;
Chicago Manual of Style (16th Edition):
Keshavarz, Behnam. “Immunodetection of Allergens from Mullet (Mugil Cephalus) and Salmon (Salmo Salar).” 2017. Doctoral Dissertation, Florida State University. Accessed April 10, 2021.
http://purl.flvc.org/fsu/fd/FSU_2017SP_Keshavarz_fsu_0071E_13780 ;.
MLA Handbook (7th Edition):
Keshavarz, Behnam. “Immunodetection of Allergens from Mullet (Mugil Cephalus) and Salmon (Salmo Salar).” 2017. Web. 10 Apr 2021.
Vancouver:
Keshavarz B. Immunodetection of Allergens from Mullet (Mugil Cephalus) and Salmon (Salmo Salar). [Internet] [Doctoral dissertation]. Florida State University; 2017. [cited 2021 Apr 10].
Available from: http://purl.flvc.org/fsu/fd/FSU_2017SP_Keshavarz_fsu_0071E_13780 ;.
Council of Science Editors:
Keshavarz B. Immunodetection of Allergens from Mullet (Mugil Cephalus) and Salmon (Salmo Salar). [Doctoral Dissertation]. Florida State University; 2017. Available from: http://purl.flvc.org/fsu/fd/FSU_2017SP_Keshavarz_fsu_0071E_13780 ;
University of Oxford
7.
Coccia, Margherita.
The role of IL-1beta in intestinal inflammation.
Degree: PhD, 2011, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:0d13f498-6470-4817-bdd2-ea6d97501f29
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558728
► Although very high levels of IL 1β are present in the intestines of patients suffering from Inflammatory Bowel Diseases (IBD), little is known about the…
(more)
▼ Although very high levels of IL 1β are present in the intestines of patients suffering from Inflammatory Bowel Diseases (IBD), little is known about the contribution of IL 1β to intestinal pathology. In the work presented in this thesis, I used several mouse models of chronic intestinal inflammation to address the role of IL 1β in driving innate and adaptive immune pathology in the intestine. My results showed that IL 1β promotes innate immune pathology in Helicobacter hepaticus triggered innate intestinal inflammation, by augmenting the recruitment of granulocytes and the accumulation and activation of a population of IFN γ and IL 17A producing innate lymphoid cells (ILC). To specifically investigate the role of IL 1R signaling on pathogenic T cell responses in the intestine, I used a T cell transfer colitis model. My results demonstrated a key role for IL 1R signals in promoting the accumulation and survival of pathogenic CD4+ T cells in the colon, particularly CD4+ IL 17A+ Th17 cells. Finally, because mutations in the NOD2 gene have been strongly associated with susceptibility to IBD, I investigated the contribution of NOD2 in the H.hepaticusinduced innate immune IBD model. I found that NOD2 expression was significantly increased in the inflamed colon. Furthermore, my preliminary studies suggested that NOD2 played a pro inflammatory role in innate immune colitis, but that NOD2 had little impact on H.hepaticus colonization of the mouse intestine. In summary, my results identify multiple mechanisms through which IL 1β promotes intestinal pathology and suggesting that targeting IL 1β, or innate immune receptors, may represent a useful therapeutic approach in IBD.
Subjects/Keywords: 616.334; Immunology; Gastroenterology; Medical Sciences
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APA (6th Edition):
Coccia, M. (2011). The role of IL-1beta in intestinal inflammation. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:0d13f498-6470-4817-bdd2-ea6d97501f29 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558728
Chicago Manual of Style (16th Edition):
Coccia, Margherita. “The role of IL-1beta in intestinal inflammation.” 2011. Doctoral Dissertation, University of Oxford. Accessed April 10, 2021.
http://ora.ox.ac.uk/objects/uuid:0d13f498-6470-4817-bdd2-ea6d97501f29 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558728.
MLA Handbook (7th Edition):
Coccia, Margherita. “The role of IL-1beta in intestinal inflammation.” 2011. Web. 10 Apr 2021.
Vancouver:
Coccia M. The role of IL-1beta in intestinal inflammation. [Internet] [Doctoral dissertation]. University of Oxford; 2011. [cited 2021 Apr 10].
Available from: http://ora.ox.ac.uk/objects/uuid:0d13f498-6470-4817-bdd2-ea6d97501f29 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558728.
Council of Science Editors:
Coccia M. The role of IL-1beta in intestinal inflammation. [Doctoral Dissertation]. University of Oxford; 2011. Available from: http://ora.ox.ac.uk/objects/uuid:0d13f498-6470-4817-bdd2-ea6d97501f29 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558728
University of Oxford
8.
Shenderov, Kevin.
Innate immune pathways controlling IL-1beta production and adjuvant-induced T helper 17 cell differentiation.
Degree: PhD, 2011, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:610114e6-c1ac-46c2-af4b-4a69659ce8b8
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770310
► Although adjuvants are critical vaccine components, their modes of action are poorly understood. This has hampered the development of novel adjuvants, and as a result…
(more)
▼ Although adjuvants are critical vaccine components, their modes of action are poorly understood. This has hampered the development of novel adjuvants, and as a result there are very few approved for clinical use. Moreover, none of the clinically-approved adjuvants are able to induce T helper 17 (Th17) CD4+ T cell responses. Th17 cells play important roles in host defense against extracellular bacteria, fungi, and some intracellular pathogens, so understanding how to produce Th17-promoting adjuvants may be valuable for vaccine development. Here, we investigated the mechanisms by which the heat-killed mycobacteria in complete Freund's adjuvant (CFA) promote T helper 17 (Th17) CD4+ T cell responses. We found that IL-1β / IL-1 receptor signaling on both CD4+ T cells and the non-T cell compartment is required for optimal CFA-induced Th17 differentiation. In addition, we demonstrated that recognition of mycobacterial trehalose dimycolate (cord factor) by mincle / CARD9-dependent signaling and of peptidoglycan by the inflammasome play major roles in adjuvant-induced IL-1β production and Th17 polarization. Importantly, purified cord factor and peptidoglycan administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA. These data suggest a strategy for the rational design of Th17-skewing adjuvants. In addition to studying IL-1β production in response to microbial stimuli, we have identified a role for endoplasmic reticulum (ER) stress in conditioning cells for IL-1β secretion in response to TLR4 stimulation. Even though the caspase 1 inflammasome is activated in this system, we found that it is dispensable for IL-1β maturation. We show that another IL-1β-cleaving enzyme, caspase 8, is activated in response to ER stress and TLR4 signaling, and may account for the inflammasome-independent processing of IL-1β. Both caspase 8 activation and IL-1β production in this system depend on the signaling adaptor TRIF. As ER stress is known to be induced by obesity and other metabolic stress, as well as during infection, the characterization of this ER stress-induced IL-1β production pathway may help illuminate the link between ER stress and inflammation.
Subjects/Keywords: Immunology; Medical Sciences; Vaccinology
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APA (6th Edition):
Shenderov, K. (2011). Innate immune pathways controlling IL-1beta production and adjuvant-induced T helper 17 cell differentiation. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:610114e6-c1ac-46c2-af4b-4a69659ce8b8 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770310
Chicago Manual of Style (16th Edition):
Shenderov, Kevin. “Innate immune pathways controlling IL-1beta production and adjuvant-induced T helper 17 cell differentiation.” 2011. Doctoral Dissertation, University of Oxford. Accessed April 10, 2021.
http://ora.ox.ac.uk/objects/uuid:610114e6-c1ac-46c2-af4b-4a69659ce8b8 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770310.
MLA Handbook (7th Edition):
Shenderov, Kevin. “Innate immune pathways controlling IL-1beta production and adjuvant-induced T helper 17 cell differentiation.” 2011. Web. 10 Apr 2021.
Vancouver:
Shenderov K. Innate immune pathways controlling IL-1beta production and adjuvant-induced T helper 17 cell differentiation. [Internet] [Doctoral dissertation]. University of Oxford; 2011. [cited 2021 Apr 10].
Available from: http://ora.ox.ac.uk/objects/uuid:610114e6-c1ac-46c2-af4b-4a69659ce8b8 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770310.
Council of Science Editors:
Shenderov K. Innate immune pathways controlling IL-1beta production and adjuvant-induced T helper 17 cell differentiation. [Doctoral Dissertation]. University of Oxford; 2011. Available from: http://ora.ox.ac.uk/objects/uuid:610114e6-c1ac-46c2-af4b-4a69659ce8b8 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770310
University of Oxford
9.
Marsay, Leanne.
Evaluation of immune correlates to TB vaccines.
Degree: PhD, 2011, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:1785050f-c963-40f9-8b97-ad008b9a769d
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572645
► Development of an improved TB vaccine is hindered by the lack of a correlate of protection. Efficacy of TB vaccines in humans can only be…
(more)
▼ Development of an improved TB vaccine is hindered by the lack of a correlate of protection. Efficacy of TB vaccines in humans can only be assessed by expensive and time consuming trials within TB endemic areas, which are limited; therefore, it is critical that vaccines with the greatest potential to protect are selected for these trials. Mycobacterial growth inhibition assays (MGIAs) have been developed with the hope that these in vitro functional assays will correlate with protection, which could aid in the selection of the best vaccine candidates. Work in this thesis describes the development and evaluation of different MGIAs for their ability to detect TB vaccine induced mycobacterial growth inhibition. The mycobacterial growth indicator tube (MGIT) MGIA reproducibly demonstrated mycobacterial growth inhibition in splenocytes from BCG vaccinated compared with naïve mice, which corresponded with in vivo protection from M. tb challenge. This assay also discriminated between PBMC from naïve and BCG/BCG-MVA85A vaccinated macaques. Microarray data showed extensive differential gene expression in splenocyte responses to ex-vivo BCG stimulation between naïve and BCG vaccinated mice. TH1 responses including IFN- with NOS2 expression were enhanced in BCG vaccinated mice, indicating a possible mechanism for mycobacterial growth inhibition in BCG vaccinated mice. Further investigation into whether the MGIT assay can be used as a correlate of protection from M. tb in humans and animals is warranted.
Subjects/Keywords: 616.995; Immunology; Medical Sciences; Vaccinology
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APA (6th Edition):
Marsay, L. (2011). Evaluation of immune correlates to TB vaccines. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:1785050f-c963-40f9-8b97-ad008b9a769d ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572645
Chicago Manual of Style (16th Edition):
Marsay, Leanne. “Evaluation of immune correlates to TB vaccines.” 2011. Doctoral Dissertation, University of Oxford. Accessed April 10, 2021.
http://ora.ox.ac.uk/objects/uuid:1785050f-c963-40f9-8b97-ad008b9a769d ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572645.
MLA Handbook (7th Edition):
Marsay, Leanne. “Evaluation of immune correlates to TB vaccines.” 2011. Web. 10 Apr 2021.
Vancouver:
Marsay L. Evaluation of immune correlates to TB vaccines. [Internet] [Doctoral dissertation]. University of Oxford; 2011. [cited 2021 Apr 10].
Available from: http://ora.ox.ac.uk/objects/uuid:1785050f-c963-40f9-8b97-ad008b9a769d ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572645.
Council of Science Editors:
Marsay L. Evaluation of immune correlates to TB vaccines. [Doctoral Dissertation]. University of Oxford; 2011. Available from: http://ora.ox.ac.uk/objects/uuid:1785050f-c963-40f9-8b97-ad008b9a769d ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572645
University of Western Ontario
10.
Wijewardhana, Chanuka.
Virally Packaged RNA in Virus-Like Particle Vaccines Enhances Antigenicity and Augments Latency Reversal of HIV-1.
Degree: 2019, University of Western Ontario
URL: https://ir.lib.uwo.ca/etd/6642
► Introduction: Since Human Immunodeficiency Virus (HIV)-1 was determined to be the etiological agent behind acquired immunodeficiency syndrome (AIDS) in 1983, numerous attempts at a cure…
(more)
▼ Introduction:
Since Human Immunodeficiency Virus (HIV)-1 was determined to be the etiological agent behind acquired immunodeficiency syndrome (AIDS) in 1983, numerous attempts at a cure have been made; however, none have been effective. One of the primary roadblocks in achieving a cure is a transcriptionally-silent latent reservoir of memory CD4+ T cells harboring HIV provirus. Combined antiretroviral therapy (cART) inhibits actively replicating virus by interfering with various stages of the replication cycle. Therefore, non-replicative viruses–like the proviruses found in latently infected cells–are hidden from the actions of continued antiretroviral therapy. As a result, cART discontinuation or treatment holidays can result in rapid viral recrudescence within days to weeks. It is thought that latency is established when HIV infects CD4 T cells that are transitioning from effector to memory status, which effectively traps the virus in an environment that is not conducive to replication due to the low metabolic activity characteristic of these cells at G0. During latency reversal, it is believed that the provirus undergoes transcriptional reactivation, allowing HIV-1 to replicate and produce infectious progeny virus that can be targeted by cART. However, a significant hurdle against the development of a vaccine against HIV is the immense viral diversity within each infected individual. A vaccine preparation should therefore encompass a near-complete repertoire of viral quasispecies to increase antigen coverage for maximal reactivation. Based on this, our group has developed a genetically diverse virus-like particle (VLP)-based vaccine, which is thought to be capable of activating a diverse array of cognate HIV-specific CD4+ T cells. These VLPs are morphologically and enzymatically identical to wild-type HIV-1; however, it contains several mutations that abrogate reverse transcription, integration, and viral RNA packaging.
Methodology:
VP and VLP antigenicity was determined as a function of i) TNFα secretion measured in cell culture supernatant of HIV– PBMC and ii) NF-κB and interferon regulatory factor (IRF) activation. Latency reversal was performed through an ex vivo DC-T-cell co-culture assay where induced HIV RNA from budded virus was quantified in cell culture supernatants following latency reversal and using an in-house developed qRT-PCR assay specific for the 5’ region of the HIV RNA. In addition, T cell activation was measured as a function of IFN-γ secretion using a commercially available ELISpot kit. To determine if immunostimulatory RNA could be preferentially packaged into VLP, 293T cells were co-transfected with a VLP-encoding plasmid and plasmids encoding for immunostimulatory RNAs. The adjuvanted VLPs were then concentrated by a combination of filtration and ultra-centrifugation with purified VLPs assayed for p24 and RNA content. Immunostimulatory potential of these RNA were measured as a function of NF-κB and IRF activation in THP-1 cells, and TNF-α and IFN-α secretion in HIV– PBMC.
Results:
VPs…
Subjects/Keywords: Medical Immunology; Medical Molecular Biology; Virus Diseases
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APA (6th Edition):
Wijewardhana, C. (2019). Virally Packaged RNA in Virus-Like Particle Vaccines Enhances Antigenicity and Augments Latency Reversal of HIV-1. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/6642
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wijewardhana, Chanuka. “Virally Packaged RNA in Virus-Like Particle Vaccines Enhances Antigenicity and Augments Latency Reversal of HIV-1.” 2019. Thesis, University of Western Ontario. Accessed April 10, 2021.
https://ir.lib.uwo.ca/etd/6642.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wijewardhana, Chanuka. “Virally Packaged RNA in Virus-Like Particle Vaccines Enhances Antigenicity and Augments Latency Reversal of HIV-1.” 2019. Web. 10 Apr 2021.
Vancouver:
Wijewardhana C. Virally Packaged RNA in Virus-Like Particle Vaccines Enhances Antigenicity and Augments Latency Reversal of HIV-1. [Internet] [Thesis]. University of Western Ontario; 2019. [cited 2021 Apr 10].
Available from: https://ir.lib.uwo.ca/etd/6642.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wijewardhana C. Virally Packaged RNA in Virus-Like Particle Vaccines Enhances Antigenicity and Augments Latency Reversal of HIV-1. [Thesis]. University of Western Ontario; 2019. Available from: https://ir.lib.uwo.ca/etd/6642
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Washington University in St. Louis
11.
Hong, Jun.
Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses.
Degree: PhD, Biology & Biomedical Sciences (Immunology), 2020, Washington University in St. Louis
URL: https://openscholarship.wustl.edu/art_sci_etds/2199
► CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells,…
(more)
▼ CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV RNA that are not cleared efficiently by adaptive immune responses. Analysis of viral tropism revealed that CHIKV RNA was present preferentially in splenic B cells and follicular dendritic cells during the persistent phase of infection, and animals lacking B cells did not develop persistent CHIKV infection in lymphoid tissue. Anti-CD137 MAb treatment resulted in T cell-dependent clearance of CHIKV RNA in lymphoid tissue, although this effect was not observed in musculoskeletal tissue. The clearance of CHIKV RNA from lymphoid tissue by anti-CD137 MAb was associated with reductions in the numbers of germinal center B cells and follicular dendritic cells. Similar results were observed with anti-CD137 MAb treatment of mice infected with Mayaro virus, a related arthritogenic alphavirus. Thus, anti-CD137 MAb treatment promotes resolution of chronic alphavirus infection in lymphoid tissues by reducing the numbers of target cells for infection and persistence. As a result of agonistic anti-CD137 MAb treatment, antibody responses to multiple T cell-dependent antigens including infectious virus, recombinant viral proteins, and conjugated haptens but not to a T cell-independent antigen or at homeostasis were impaired. These effects were not due to enhanced apoptosis or impaired proliferation of B cells but instead correlated with changes in lymphoid follicle structure and GC B cell dispersal, and were mediated by CD137 signaling in CD4+ and CD8+ T cells. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may cause GC collapse and impair long-term antibody and B cell memory responses.
Advisors/Committee Members: Michael S. Diamond, Paul M. Allen, Anthony R. French, Deborah J. Lenschow, Adrianus Boon.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA (6th Edition):
Hong, J. (2020). Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/2199
Chicago Manual of Style (16th Edition):
Hong, Jun. “Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses.” 2020. Doctoral Dissertation, Washington University in St. Louis. Accessed April 10, 2021.
https://openscholarship.wustl.edu/art_sci_etds/2199.
MLA Handbook (7th Edition):
Hong, Jun. “Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses.” 2020. Web. 10 Apr 2021.
Vancouver:
Hong J. Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2020. [cited 2021 Apr 10].
Available from: https://openscholarship.wustl.edu/art_sci_etds/2199.
Council of Science Editors:
Hong J. Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses. [Doctoral Dissertation]. Washington University in St. Louis; 2020. Available from: https://openscholarship.wustl.edu/art_sci_etds/2199
Washington University in St. Louis
12.
Verbaro, Daniel.
Epigenetic and Signaling Pathways Regulating the Maintenance of CD8 T Cell Identity and Function.
Degree: PhD, Biology & Biomedical Sciences (Immunology), 2020, Washington University in St. Louis
URL: https://openscholarship.wustl.edu/art_sci_etds/2249
► In response to infection, antigen specific CD4 and CD8 T cells rapidly divide to provide help to the immune system and promote cytotoxicity of infected…
(more)
▼ In response to infection, antigen specific CD4 and CD8 T cells rapidly divide to provide help to the immune system and promote cytotoxicity of infected cells, respectively. Through this rapid division, CD4 and CD8 T cells maintain silencing of the opposing lineage’s genes, which is essential to acutely eliminating pathogens. However, not all pathogens are acutely eliminated even when silencing is maintained, and the pathogen persists in the presence of activated CD8 T cells. CD8 T cells chronically exposed to antigen are phenotypically different than CD8 T cells acutely exposed to antigen, but CD8 T cell still exert control over chronic infections and cancers. Two unanswered questions regarding the maintenance CD8 T cell responses are: 1. How do CD8 T cells maintain the silencing of alternative lineage genes through division in the periphery, and 2. How do these cells maintain viral control through chronic stimulation. To shed light on these questions, two specific aims were developed for this thesis. The first specific aim was to determine whether the epigenetic factor G9a is required to maintain silencing of helper lineage genes in proliferating CD8 T cells. To this end, genetic deletion of G9a in CD8 T cells resulted in de-repression of Cd4 and other helper T-related genes during lymphopenia- or tumor antigen-induced proliferation. In response to Listeria monocytogenes infection, G9a deficient CD8 T cells maintained silencing of Cd4. These data highlight that proliferating CD8 T cells employ multiple gene silencing mechanisms including G9a–mediated epigenetic modifications to maintain silencing of T helper-associated genes. The second specific aim of this study was to determine how increasing PI3K signaling affects the maintenance of a functional CD8 T cell pool during chronic viral stimulation. During chronic Lymphocytic choriomeningtis virus (LCMV) infection, overexpression of a constitutively active form of PI3K in CD8 T cells caused lethal immunopathology reminiscent of chronic infection of PDL1 knockout mice. Inducible overexpression of PI3K after CD8 T cell priming depleted the memory- and stem-like CD8 T cell pool, which is required to sustain the CD8 T cell response. These data highlight an epistatic relationship between PI3K and PD1 in chronic CD8 T cells, and inhibitory signals may protect the chronic CD8 T cell progenitors from depletion throughout the course of infection. Future work will determine whether the responsiveness of CD8 T cells to PI3K signaling or PD1 blockade requires the transcription factor AP4.
Advisors/Committee Members: Takeshi Egawa, Paul Allen, Marco Colonna, Eugene Oltz, Haina Shin.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA (6th Edition):
Verbaro, D. (2020). Epigenetic and Signaling Pathways Regulating the Maintenance of CD8 T Cell Identity and Function. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/2249
Chicago Manual of Style (16th Edition):
Verbaro, Daniel. “Epigenetic and Signaling Pathways Regulating the Maintenance of CD8 T Cell Identity and Function.” 2020. Doctoral Dissertation, Washington University in St. Louis. Accessed April 10, 2021.
https://openscholarship.wustl.edu/art_sci_etds/2249.
MLA Handbook (7th Edition):
Verbaro, Daniel. “Epigenetic and Signaling Pathways Regulating the Maintenance of CD8 T Cell Identity and Function.” 2020. Web. 10 Apr 2021.
Vancouver:
Verbaro D. Epigenetic and Signaling Pathways Regulating the Maintenance of CD8 T Cell Identity and Function. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2020. [cited 2021 Apr 10].
Available from: https://openscholarship.wustl.edu/art_sci_etds/2249.
Council of Science Editors:
Verbaro D. Epigenetic and Signaling Pathways Regulating the Maintenance of CD8 T Cell Identity and Function. [Doctoral Dissertation]. Washington University in St. Louis; 2020. Available from: https://openscholarship.wustl.edu/art_sci_etds/2249
Washington University in St. Louis
13.
Bern, Michael.
In Vivo Mechanisms of Natural Killer Cell Tolerance.
Degree: PhD, Biology & Biomedical Sciences (Immunology), 2020, Washington University in St. Louis
URL: https://openscholarship.wustl.edu/art_sci_etds/2167
► Natural killer (NK) cells are cytotoxic innate immune cells that provide protection from pathogens and tumors. To carry out these functions, NK cells must distinguish…
(more)
▼ Natural killer (NK) cells are cytotoxic innate immune cells that provide protection from pathogens and tumors. To carry out these functions, NK cells must distinguish between healthy and unhealthy self-cells. Inability to recognize stressed cells would lead to a failure of NK-cell immunity whereas inability to identify healthy cells could lead to NK-cell autoimmunity. It remains unclear, however, how NK cells are able to distinguish healthy and unhealthy self-cells with a limited repertoire of germline-encoded receptors. The "missing-self" hypothesis proposes that NK cells identify stressed cells by their reduced expression of MHC class I (MHC-I) that is almost ubiquitously expressed as self. NK cells express inhibitory Ly49 receptors that bind to MHC-I and inhibit NK cells from killing healthy cells, and downregulation of MHC-I on stressed cells leads to loss of inhibition and killing by missing-self recognition. The importance of Ly49 receptors and MHC-I for maintaining NK-cell self-tolerance, however, has only been suggested by in vitro experiments and correlative in vivo experiments. Here we generated a mouse with a mutation in the immunoreceptor tyrosine-based inhibitory motif of Ly49A and another mouse with an allele of the gene for beta2-microglobulin containing loxP sites (B2m fl) to directly test the roles of Ly49s and MHC-I in NK cell self-tolerance in vivo. Loss of inhibitory signaling through a mutant Ly49 or global MHC-I downregulation induced changes in NK-cell responsiveness or inhibitory receptor expression that maintained NK-cell self-tolerance. In contrast, downregulation of MHC-I on CD4+ T cells, led to a subtle loss of CD4+ T cells, but NK cells remained tolerant to a substantial population of MHC-I-deficient CD4+ T cells without altering their responsiveness or receptor repertoire. In this setting, infection with murine cytomegalovirus or treatment with a toll-like receptor agonist induced NK cell-mediated rejection of MHC-I-deficient CD4+ T cells. These results show that loss of inhibitory signaling to NK cells in vivo can induce tolerance or rejection of missing-self in different contexts and that inflammation promotes missing-self reactivity.
Advisors/Committee Members: Wayne M. Yokoyama, Paul M. Allen, Marco Colonna, Takeshi Egawa, Todd A. Fehniger.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA (6th Edition):
Bern, M. (2020). In Vivo Mechanisms of Natural Killer Cell Tolerance. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/2167
Chicago Manual of Style (16th Edition):
Bern, Michael. “In Vivo Mechanisms of Natural Killer Cell Tolerance.” 2020. Doctoral Dissertation, Washington University in St. Louis. Accessed April 10, 2021.
https://openscholarship.wustl.edu/art_sci_etds/2167.
MLA Handbook (7th Edition):
Bern, Michael. “In Vivo Mechanisms of Natural Killer Cell Tolerance.” 2020. Web. 10 Apr 2021.
Vancouver:
Bern M. In Vivo Mechanisms of Natural Killer Cell Tolerance. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2020. [cited 2021 Apr 10].
Available from: https://openscholarship.wustl.edu/art_sci_etds/2167.
Council of Science Editors:
Bern M. In Vivo Mechanisms of Natural Killer Cell Tolerance. [Doctoral Dissertation]. Washington University in St. Louis; 2020. Available from: https://openscholarship.wustl.edu/art_sci_etds/2167
14.
Wymore Brand, Meghan Joyce.
Age-related impact of proteobacteria colonization on mucosal homeostasis and the microbial community in gastrointestinal health and disease.
Degree: 2017, Iowa State University
URL: https://lib.dr.iastate.edu/etd/16112
► Inflammatory bowel disease is a group of chronic intestinal inflammatory disorders with a complex etiology, and has been associated with a microbial dysbiosis and presence…
(more)
▼ Inflammatory bowel disease is a group of chronic intestinal inflammatory disorders with a complex etiology, and has been associated with a microbial dysbiosis and presence of GI pathogens including adherent and invasive Escherichia coli (AIEC) and Campylobacter. A gnotobiotic murine model (altered Schaedler flora, ASF) devoid of proteobacteria was utilized to evaluate microbial and host responses after colonization with AIEC LF82, E. coli Nissle 1917, and C. jejuni alone or treated with dextran sodium sulfate (DSS). The ultimate goal of this research was to understand the effects on mucosal homeostasis after disturbance of the resident microbiota by proteobacterial pathobionts. As few studies have evaluated the stability of the microbiota over multiple generations, Chapter 3 evaluates the impact of AIEC LF82 colonization on the heritability/transmissibility of the ASF over multiple generations. Results indicated minimal changes in ASF abundance within a generation, but there was a significant shift in the microbial population when comparing early and later generations. As early-life microbial exposures have been demonstrated to influence mucosal homeostasis later in life, Chapter 4 describes changes in the sensitivity to colitis following E. coli LF82 colonization of ASF mice as an adult or neonate. We demonstrate neonatal colonization with LF82 increases the susceptibility to colitis, with increased inflammatory responses and minimal microbial changes, with neonatal colonization inducing subclinical, chronic inflammation that may predispose to more severe inflammation. In Chapter 5 of this dissertation, the benefits associated with probiotic Escherichia coli Nissle 1917 (EcN) colonization of neonatal mice to prevent or attenuate colitis as described in Chapter 4 were evaluated. Results indicated that co-colonization of neonatal mice with EcN did not impact the severity of colitis, but did reduce the host’s proinflammatory cytokine response. Finally, in Chapter 6, both conventional and gnotobiotic mice were used to demonstrate that the pathogenesis of C. jejuni is differentially influenced by the complexity of the microbiota. By investigating host-microbial relationships and their effects on intestinal homeostasis, this work provided insights into the underlying mechanisms contributing to the onset of inflammatory bowel disease, as well as what constitutes a ‘healthy’ state in the relationship with our gut microbiota.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA (6th Edition):
Wymore Brand, M. J. (2017). Age-related impact of proteobacteria colonization on mucosal homeostasis and the microbial community in gastrointestinal health and disease. (Thesis). Iowa State University. Retrieved from https://lib.dr.iastate.edu/etd/16112
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wymore Brand, Meghan Joyce. “Age-related impact of proteobacteria colonization on mucosal homeostasis and the microbial community in gastrointestinal health and disease.” 2017. Thesis, Iowa State University. Accessed April 10, 2021.
https://lib.dr.iastate.edu/etd/16112.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wymore Brand, Meghan Joyce. “Age-related impact of proteobacteria colonization on mucosal homeostasis and the microbial community in gastrointestinal health and disease.” 2017. Web. 10 Apr 2021.
Vancouver:
Wymore Brand MJ. Age-related impact of proteobacteria colonization on mucosal homeostasis and the microbial community in gastrointestinal health and disease. [Internet] [Thesis]. Iowa State University; 2017. [cited 2021 Apr 10].
Available from: https://lib.dr.iastate.edu/etd/16112.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wymore Brand MJ. Age-related impact of proteobacteria colonization on mucosal homeostasis and the microbial community in gastrointestinal health and disease. [Thesis]. Iowa State University; 2017. Available from: https://lib.dr.iastate.edu/etd/16112
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Iowa State University
15.
O'Neill, Kevin Charles.
Efficacy and impact of current commercial porcine circovirus type 2 (PCV2) vaccines in dams and growing pigs.
Degree: 2012, Iowa State University
URL: https://lib.dr.iastate.edu/etd/12837
► Porcine circovirus (PCV) was initially described as a contaminant of the continuous porcine kidney cell line PK-15 in 1974 (Tischer et al., 1974). It is…
(more)
▼ Porcine circovirus (PCV) was initially described as a contaminant of the continuous porcine kidney cell line PK-15 in 1974 (Tischer et al., 1974). It is a covalently closed single-stranded DNA virus belonging to the genus Circovirus in the family Circoviridae (Tischer et al., 1982). In early studies it was determined that PCV is ubiquitous, but non-pathogenic (Tischer et al., 1986). In 1991, a severe wasting disorder was observed in pigs shortly after weaning in western Canada (Harding et al., 1997; Clark, 1997), the United States (Allan et al., 1998b), and Europe (LeCann et al., 1997; Allan et al., 1998b). Although PCV was identified in tissues from affected pigs, it was determined to differ from the original PCV genome by 24% to 32% (Meehan et al., 1998; Cheung et al., 2007). This led to classification of PCV into two distinct genotypes: the original non-pathogenic strain or PCV type 1 (PCV1) and the newly isolated, pathogenic strain or PCV type 2 (PCV2) (Meehan et al., 1998). Further genomic alignments revealed that PCV2 could be separated into two distinct groups: group 1 comprised of three distinct clusters (1A to 1C), and group 2 comprised of five distinct clusters (2A to 2E) (Olvera et al., 2007). Due to multiple designations for these groups (de Boisseson C. et al., 2004; Olvera et al., 2007; Timmusk et al., 2008; Grau-Roma et al., 2008; Carman et al., 2008), use of lower case letter designations for each group was proposed by Segalés et al. (2008) for uniformity, resulting PCV2 group 1 becoming PCV2a and PCV2 group 2 becoming PCV2b (Segalés et al., 2008).
Since its original identification as the etiological agent of postweaning multisystemic wasting syndrome (PMWS) (Ellis et al., 1998; Meehan et al., 1998; Allan et al., 1998a), PCV2 has been associated with multiple disease manifestations, collectively referred to as PCV-associated disease (PCVAD) (Opriessnig et al., 2007). Besides PMWS (Clark, 1997; Harding et al., 1998), these disease manifestations include respiratory disease (Kim et al., 2003), enteric disease (Kim et al., 2004), reproductive failure (West et al., 1999), and porcine dermatitis and nephropathy syndrome (PDNS) (Choi et al., 2001). All are considered of high economic importance due to their contribution to ill-thriftiness, morbidity rates varying between 12.5% and 59% (USDA, 2008), and variable mortality rates (López-Soria et al., 2005; Calsamiglia et al., 2007; Alarcon et al., 2011; Grau-Roma et al., 2012).
PCV2 is considered ubiquitous and is prevalent globally (Tischer et al., 1986; Dulac et al., 1989; Edwards et al., 1994; Allan et al., 2000; Walker et al., 2000; Zhou et al., 2006; Segalés et al., 2008) due to both its resilience to inactivation methods (Allan et al., 1994; Welch et al., 2006; O'Dea et al., 2008) and its numerous methods of transmission. These include horizontal transmission routes such as colostrum (Shibata et al., 2006), feces (Shibata et al., 2003), invertebrate vectors (Blunt et al., 2011), nasal secretions (Shibata et al., 2003), oral secretions (Shibata et al.,…
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Veterinary Medicine
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APA (6th Edition):
O'Neill, K. C. (2012). Efficacy and impact of current commercial porcine circovirus type 2 (PCV2) vaccines in dams and growing pigs. (Thesis). Iowa State University. Retrieved from https://lib.dr.iastate.edu/etd/12837
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
O'Neill, Kevin Charles. “Efficacy and impact of current commercial porcine circovirus type 2 (PCV2) vaccines in dams and growing pigs.” 2012. Thesis, Iowa State University. Accessed April 10, 2021.
https://lib.dr.iastate.edu/etd/12837.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
O'Neill, Kevin Charles. “Efficacy and impact of current commercial porcine circovirus type 2 (PCV2) vaccines in dams and growing pigs.” 2012. Web. 10 Apr 2021.
Vancouver:
O'Neill KC. Efficacy and impact of current commercial porcine circovirus type 2 (PCV2) vaccines in dams and growing pigs. [Internet] [Thesis]. Iowa State University; 2012. [cited 2021 Apr 10].
Available from: https://lib.dr.iastate.edu/etd/12837.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
O'Neill KC. Efficacy and impact of current commercial porcine circovirus type 2 (PCV2) vaccines in dams and growing pigs. [Thesis]. Iowa State University; 2012. Available from: https://lib.dr.iastate.edu/etd/12837
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
16.
Obeng-Adjei, Nyamekye.
Investigating and Manipulating Immune Responses to Hepatotropic Pathogens Using Synthetic DNA.
Degree: 2013, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/679
► Hepatotropic pathogens, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV) and malaria Plasmodium often escape cellular immune clearance, resulting in chronic infections. With…
(more)
▼ Hepatotropic pathogens, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV) and malaria Plasmodium often escape cellular immune clearance, resulting in chronic infections. With billions at the risk of infection, the need for an immune therapy that will incite protective immune responses against these pathogens is more important now than ever. To develop effective therapies against these pathogens, it is important to understand the mechanisms by which liver-primed CD8 T cells become defective. In this report, I directly compared liver-primed CD8 T cells to secondary lymphoid tissue-primed CD8 T cells for differentiation, function, and memory programming in a highly controlled fashion. We used hydrodynamic tail vain injection of synthetic plasmids to establish liver-specific antigen expression in the P14 transgenic mouse model, and studied the priming of CD8 T cells. Intrahepatically activated CD8 T cells exhibited unique expansion, memory differentiation, polyfunctionality and cytotoxicity compared to T cells primed in the periphery. The difference in their expansion resulted in lower memory CTL frequency, which led to reduced protection against lethal viral challenge. These results demonstrated that defective liver priming of naïve CD8 T cells contributes to the lower frequency of antigen-specific CTLs observed during liver infection in HBV and
HCV patients, which helps these pathogens to escape immune clearance.
The results from the study provide evidence that, the eradication of HBV and HCV infected hepatocytes will require both the induction of a strong antigen-specific immune
response and the subsequent deployment of that response towards the liver. We therefore assessed the ability of a synthetic DNA vaccine encoding a recombinant plasmid of the HBcAg and HBsAg to drive immunity in the liver. Intramuscular vaccination accompanied by electroporation induced both strong antigen-specific T cell and high titer antibody responses systematically and in the liver. Furthermore, immunized mice showed strong cytotoxic responses that eliminate adoptively transferred HBV-coated target cells in the spleen and liver. These data provide important insight into the generation of peripheral immune responses that are recruited to the liver; an approach that could be beneficial in the search for vaccines or immune-therapies for liver disease.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Pathology; Pharmacology
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APA (6th Edition):
Obeng-Adjei, N. (2013). Investigating and Manipulating Immune Responses to Hepatotropic Pathogens Using Synthetic DNA. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/679
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Obeng-Adjei, Nyamekye. “Investigating and Manipulating Immune Responses to Hepatotropic Pathogens Using Synthetic DNA.” 2013. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/679.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Obeng-Adjei, Nyamekye. “Investigating and Manipulating Immune Responses to Hepatotropic Pathogens Using Synthetic DNA.” 2013. Web. 10 Apr 2021.
Vancouver:
Obeng-Adjei N. Investigating and Manipulating Immune Responses to Hepatotropic Pathogens Using Synthetic DNA. [Internet] [Thesis]. University of Pennsylvania; 2013. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/679.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Obeng-Adjei N. Investigating and Manipulating Immune Responses to Hepatotropic Pathogens Using Synthetic DNA. [Thesis]. University of Pennsylvania; 2013. Available from: https://repository.upenn.edu/edissertations/679
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
17.
O'Hara, Aisling Catherine.
Impact of IL-27 on regulatory T cell responses.
Degree: 2013, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/906
► Interleukin (IL)–27 is a heterodimeric cytokine with potent inhibitory properties. Thus, mice that lack IL–27–mediated signaling develop exaggerated inflammatory responses during toxoplasmosis as well as…
(more)
▼ Interleukin (IL)–27 is a heterodimeric cytokine with potent inhibitory properties. Thus, mice that lack IL–27–mediated signaling develop exaggerated inflammatory responses during toxoplasmosis as well as other infections or autoimmune processes. While regulatory T (Treg) cells are critical to limit inflammation, their role during toxoplasmosis is controversial because this infection results in a dramatic decrease in the total numbers of these cells associated with reduced levels of IL–2. Because IL–27 suppresses IL–2, we initially hypothesized that it was responsible for the Treg cell “crash”. Thus, we examined the role of IL–27 and IL–2 and their effects on Treg cells during toxoplasmosis. We observed that although IL–2 production is enhanced in the absence of IL–27, this was not sufficient to rescue Treg cell frequencies during infection. Rather, our data indicated that IL–27 promoted an immunosuppressive Treg cell population that displayed a T helper 1 (TH1) phenotype, characterized by the expression of T–bet, CXCR3, IL–10 and interferon (IFN)–γ. Although IFN–γ and IL–27 can give rise to a population of T–bet+ Treg cells in vitro, there were distinct differences in the signaling and transcriptional responses of Treg cells to these cytokines. Analysis of the genes induced by IL–27 revealed that it promoted Treg cell expression of a number of inhibitory receptors such as LAG–3 and PD–1 which function to limit the magnitude of T cell responses. Taken together, these studies highlight the role of IL–27 as a central coordinator of Treg cell effector functions during inflammation.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA ·
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CSE |
Export
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APA (6th Edition):
O'Hara, A. C. (2013). Impact of IL-27 on regulatory T cell responses. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/906
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
O'Hara, Aisling Catherine. “Impact of IL-27 on regulatory T cell responses.” 2013. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/906.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
O'Hara, Aisling Catherine. “Impact of IL-27 on regulatory T cell responses.” 2013. Web. 10 Apr 2021.
Vancouver:
O'Hara AC. Impact of IL-27 on regulatory T cell responses. [Internet] [Thesis]. University of Pennsylvania; 2013. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/906.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
O'Hara AC. Impact of IL-27 on regulatory T cell responses. [Thesis]. University of Pennsylvania; 2013. Available from: https://repository.upenn.edu/edissertations/906
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
18.
Zhao, Jiangyang.
Epigenetic Activation of the Mouse T Cell Receptor Beta Recombination Center.
Degree: PhD, Biology & Biomedical Sciences (Molecular Genetics & Genomics), 2017, Washington University in St. Louis
URL: https://openscholarship.wustl.edu/art_sci_etds/1157
► Lymphocytes are the work horses of adaptive immunity. Compared to the B lymphocyte lineage, early stage progenitors of T lymphocytes maintain considerable potential for differentiation…
(more)
▼ Lymphocytes are the work horses of adaptive immunity. Compared to the B lymphocyte lineage, early stage progenitors of T lymphocytes maintain considerable potential for differentiation into other hematopoietic lineages. T lineage commitment requires the continuous coordination of transcription factors (TFs) by Notch1 signaling after multi-potent progenitors (MPPs) migrate to thymus. One of the first hall marks of T lineage commitment is expression of the T cell receptor β (TCRβ), which is encoded by the Tcrb locus following its assembly by V(D)J recombination, a somatic shuffling of the genome that joins one V, one D, and one J gene segment. Tcrb assembly is initiated at its recombination center (RC), composed of two DβJβ clusters. Tcrb-RC exhibits features of regulatory regions called super-enhancers (SEs), which are characterized by high level of active histone mark, H3K27ac, and by clusters of binding for TFs involved in cell fate decisions. A key Tcrb-RC enhancer, called Eβ, harbors two composite ETS1-RUNX1 binding motifs, which widely exist in regulatory elements for genes involved in T lymphopoiesis. ETS1 is sharply upregulated during T cell lineage commitment and recruits constitutively expressed RUNX1 to Eβ. However, the independent roles of these two TFs remain unclear, especially since both are potent transactivators. In this study, I have shown that both ETS1 and RUNX1 are sufficient to independently activate Eβ in extrachromosomal reporter substrates. However, ETS1 by itself fails to activate Eβ in its native chromosomal context. By contrast, RUNX1 is sufficient to activate the endogenous Eβ element and its neighboring 25 kb region independently from ETS1. In addition, RUNX1 is sufficient to mediate long-range promoter-Eβ interactions, nucleosome clearance, and robust transcription throughout the Tcrb recombination center (RC). We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding (NRDB), can compensate for loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of RC promoters.
Advisors/Committee Members: Eugene M. Oltz, Shiming Chen, Takeshi Egawa, Jason Mills, Barry Sleckman.
Subjects/Keywords: Allergy and Immunology; Genetics; Immunology and Infectious Disease; Medical Immunology
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Zhao, J. (2017). Epigenetic Activation of the Mouse T Cell Receptor Beta Recombination Center. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/1157
Chicago Manual of Style (16th Edition):
Zhao, Jiangyang. “Epigenetic Activation of the Mouse T Cell Receptor Beta Recombination Center.” 2017. Doctoral Dissertation, Washington University in St. Louis. Accessed April 10, 2021.
https://openscholarship.wustl.edu/art_sci_etds/1157.
MLA Handbook (7th Edition):
Zhao, Jiangyang. “Epigenetic Activation of the Mouse T Cell Receptor Beta Recombination Center.” 2017. Web. 10 Apr 2021.
Vancouver:
Zhao J. Epigenetic Activation of the Mouse T Cell Receptor Beta Recombination Center. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2017. [cited 2021 Apr 10].
Available from: https://openscholarship.wustl.edu/art_sci_etds/1157.
Council of Science Editors:
Zhao J. Epigenetic Activation of the Mouse T Cell Receptor Beta Recombination Center. [Doctoral Dissertation]. Washington University in St. Louis; 2017. Available from: https://openscholarship.wustl.edu/art_sci_etds/1157
19.
Fernandez, Estefania.
Characterizing the Humoral Response to Flavivirus Infection.
Degree: PhD, Biology & Biomedical Sciences (Immunology), 2019, Washington University in St. Louis
URL: https://openscholarship.wustl.edu/art_sci_etds/1775
► Flaviviruses are positive (+) sense, single-stranded RNA viruses of the Flaviviridae family that are transmitted by mosquitoes. For our studies, we focused on Zika…
(more)
▼ Flaviviruses are positive (+) sense, single-stranded RNA viruses of the Flaviviridae family that are transmitted by mosquitoes. For our studies, we focused on Zika virus (ZIKV) and Japanese encephalitis virus (JEV). Most human infections with ZIKV historically resulted in a mild self-limiting febrile illness. However, since 2013, a worldwide spread and increase in ZIKV infections has been observed. Notably, ZIKV has been associated with autoimmune ascending paralysis (Guillain-Barré Syndrome) and ophthalmologic effects in adults and intrauterine growth restriction and microcephaly in developing fetuses. Current vaccine efforts utilize technologies implemented for related flaviviruses (yellow fever virus (YFV), Dengue virus (DENV), and JEV) including subunit-based, chemically inactivated, and live-attenuated vaccines. Furthermore, co-circulation of flaviviruses, such as DENV and ZIKV in regions of South America, make it desirable to generate a vaccine that protects against both. JEV infections are usually clinically asymptomatic or result in a mild self-limiting febrile illness. However, disseminated infection and viral penetration of the blood-brain barrier into the central nervous system results in meningitis and encephalitis, which are associated with high morbidity and mortality. Children are especially vulnerable to neuroinvasion due to lack of prior immunity and the relative immaturity of their immune responses. Although vaccination programs in endemic countries have decreased the incidence of disease, existing vaccines have limitations including multiple dose requirements and reactogenicity. Finally, a major issue in vaccine efficacy is the derivation from genotype III (GIII) strains, the concurrent diversity of JEV worldwide, and the scarcity of efficacy testing across multiple genotypes. Currently, there are five genotypes of JEV that encompass approximately 100 unique strains. In addition, the dominant genotypes vary by country and are not static over time. We are interested in understanding the immunologic restriction of flavivirus infection by characterizing the interaction between viruses and the humoral response. We identified a panel of mouse and human derived anti-ZIKV monoclonal mAbs and found that ZIKV specific mAbs strongly neutralize multiple strains of ZIKV of Asian and African lineages compared to mAbs that recognize a cross-reactive determinant. Additionally, we identified a novel conformational inter-dimer epitope that when bound, results in significant reduction in in vitro infection and in vivo protection. We tested the prophylactic and therapeutic efficacy of the strongest neutralizing mAbs in adult male mice for lethality and pregnant female mice for transplacental protection of fetuses. We also tested a panel of anti-DENV mAbs derived from naturally infected patients. We confirmed that EDE1 mAbs, which have stronger virus binding in the absence of glycosylation compared to EDE2 mAbs, are more potent neutralizers of multiple ZIKV strains. We demonstrated that viral seeding…
Advisors/Committee Members: Michael S. Diamond, Daved H. Fremont, Robyn S. Klein, Gene Oltz, Haina Shin.
Subjects/Keywords: JEV, ZIKV; Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA ·
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APA (6th Edition):
Fernandez, E. (2019). Characterizing the Humoral Response to Flavivirus Infection. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/1775
Chicago Manual of Style (16th Edition):
Fernandez, Estefania. “Characterizing the Humoral Response to Flavivirus Infection.” 2019. Doctoral Dissertation, Washington University in St. Louis. Accessed April 10, 2021.
https://openscholarship.wustl.edu/art_sci_etds/1775.
MLA Handbook (7th Edition):
Fernandez, Estefania. “Characterizing the Humoral Response to Flavivirus Infection.” 2019. Web. 10 Apr 2021.
Vancouver:
Fernandez E. Characterizing the Humoral Response to Flavivirus Infection. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2019. [cited 2021 Apr 10].
Available from: https://openscholarship.wustl.edu/art_sci_etds/1775.
Council of Science Editors:
Fernandez E. Characterizing the Humoral Response to Flavivirus Infection. [Doctoral Dissertation]. Washington University in St. Louis; 2019. Available from: https://openscholarship.wustl.edu/art_sci_etds/1775
University of Pennsylvania
20.
Naradikian, Martin Souren.
Interplay of Il-4, Il-21, and Ifnγ on Memory B Cell Fate Decisions.
Degree: 2016, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/1909
► The ability to establish a durable pool of memory B (BMEM) cells is not only a key feature of adaptive immunity but also critical for…
(more)
▼ The ability to establish a durable pool of memory B (BMEM) cells is not only a key feature of adaptive immunity but also critical for host survival upon secondary infection. Depending on the nature of the pathogen, preimmune B cells differentiate into various BMEM cells associated with a particular immunoglobulin isotype. Moreover, cytokines dictate this process via the induction of transcription factors resulting in a stable lineage. Recently, the transcription factor, T-BET, has been implicated in reinforcing BMEM cells of the IgG2c isotype. Further, phenotypically similar cells express the integrin, CD11c, and appear in humoral autoimmunity and aged mice. However, the activation requisites and extrinsic cues driving T-BET and CD11c expression remain poorly defined. T follicular helper (TFH) cells instruct B cells to adopt various BMEM cell fates via the production of cytokines—specifically IL-4, IL-21 and IFNγ. Here we reveal a novel interplay among these cytokines in determining T-BET+ B cell fate. We find that IL-21 or IFNγ directly promote T-BET+ B cells in the context of TLR engagement. Further, IL-4 antagonizes IL-21-induced T-BET expression, but augments that of IFNγ. Finally, IL-21, but not IFNγ, promotes CD11c expression. Using well-defined infections that drive IL-21 and robust IFNγ or IL-4 production, we show that these same cytokine interactions function in vivo to determine T-BET and CD11c expression. We elaborate a model in which abundant IFNγ will drive T-BET+ B cells; however, in the absence of IFNγ, IL-21 and IL-4 reciprocally regulate both T-BET and CD11c. Importantly, CD11c expression is restricted to BMEM cells, which phenotypically resemble Age-associated B cells (ABCs). In accord with our infection results, we show that T-BET+CD11c+ ABCs are likely a pool BMEM cells. Consistent with this idea, ABCs are somatically mutated, class- switched, and require the ability to present antigen and receive costimulation to form. These findings suggest that T-BET+ B cells seen in health and autoimmunity share the common initiating features of TLR driven activation within this circumscribed cytokine milieu.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA (6th Edition):
Naradikian, M. S. (2016). Interplay of Il-4, Il-21, and Ifnγ on Memory B Cell Fate Decisions. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/1909
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Naradikian, Martin Souren. “Interplay of Il-4, Il-21, and Ifnγ on Memory B Cell Fate Decisions.” 2016. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/1909.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Naradikian, Martin Souren. “Interplay of Il-4, Il-21, and Ifnγ on Memory B Cell Fate Decisions.” 2016. Web. 10 Apr 2021.
Vancouver:
Naradikian MS. Interplay of Il-4, Il-21, and Ifnγ on Memory B Cell Fate Decisions. [Internet] [Thesis]. University of Pennsylvania; 2016. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/1909.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Naradikian MS. Interplay of Il-4, Il-21, and Ifnγ on Memory B Cell Fate Decisions. [Thesis]. University of Pennsylvania; 2016. Available from: https://repository.upenn.edu/edissertations/1909
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
21.
Rao, Sheila.
Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function.
Degree: 2013, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/917
► Upon invasion of microbial pathogens, cells of the innate immune system respond through the activation of pattern recognition receptors (PRRs) that recognize pattern associated molecular…
(more)
▼ Upon invasion of microbial pathogens, cells of the innate immune system respond through the activation of pattern recognition receptors (PRRs) that recognize pattern associated molecular patterns (PAMPs). Once these receptors bind ligand, they initiate a signaling cascade culminating in the expression of proinflammatory and antiviral cytokines, costimulatory molecules, and antimicrobial agents, all of which contribute to pathogen clearance and host defense. However, excessive signaling through these receptors can lead to inflammatory conditions resulting in damage to the host. Therefore, understanding the signaling events downstream of PRR activation is critical for gaining insight into targeting specific mediators for therapeutic intervention to combat infection and to limit host pathology. Canonically, Toll-like receptors (TLRs), one class of PRR, have been thought to signal through serine threonine kinases following ligand recognition. However, there is emerging evidence for the role of protein tyrosine kinases regulating TLR function, but their role is not entirely clear. We sought to understand how TLR9 function is affected by a conserved tyrosine residue in its cytoplasmic domain and by activation of the protein tyrosine kinase Syk. We initially hypothesized that Syk might be participating in tyrosine phosphorylation of TLR9 to induce downstream signaling following receptor activation with CpG DNA. Utilizing genetic deletion of Syk in dendritic cells in vivo and genetic knockdown in a macrophage cell line, here we demonstrate that Syk is important for the intracellular trafficking and exocytosis of the proinflammatory cytokine TNFa, but not IL-6, following CpG stimulation. This secretion event involved activation of calcium signaling and calcium calmodulin kinase II (CaMKII) downstream of Syk. Syk-deficient cells exhibited normal CpG-induced activation of the canonical TLR9 signaling machinery, suggesting that Syk mediates a signaling cascade to promote cytokine exocytosis independent of cytokine transcription and translation, a role unexpected based on its function downstream of ITAM-bearing receptors. These data implicate this signaling pathway in a novel role of cytokine sorting and may have broader implications for release of other cytokines downstream of various pattern recognition receptors.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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Export
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APA (6th Edition):
Rao, S. (2013). Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/917
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Rao, Sheila. “Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function.” 2013. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/917.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Rao, Sheila. “Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function.” 2013. Web. 10 Apr 2021.
Vancouver:
Rao S. Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function. [Internet] [Thesis]. University of Pennsylvania; 2013. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/917.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Rao S. Tyrosine Phosphorylation and Structural Requirements Mediate Toll-Like Receptor 9 Function. [Thesis]. University of Pennsylvania; 2013. Available from: https://repository.upenn.edu/edissertations/917
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
22.
Swanstrom, Adrienne E.
Dissociating Siv Env and Cd4: Consequenes for Virus and Host.
Degree: 2015, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/2048
► CD4 tropism is conserved among all primate lentiviruses and likely contributes to viral pathogenesis by targeting cells that are critical for the adaptive anti-viral immune…
(more)
▼ CD4 tropism is conserved among all primate lentiviruses and likely contributes to viral pathogenesis by targeting cells that are critical for the adaptive anti-viral immune responses. Although CD4-independent variants of HIV and SIV have been described that can utilize coreceptors CCR5 or CXCR4 in the absence of CD4, these viruses typically retain their CD4 binding sites and can still interact with CD4. In this thesis, I present the characterization and evaluation, both in vitro and in vivo, of a novel CD4-independent variant of SIV lacking a CD4 binding site.
I first describe the derivation of iMac239, a CD4-independent variant of SIVmac239. Like other CD4-independent variants, we found that a mutation in the V1/V2 loops of Env was required for CD4-independent entry, and that acquisition of CD4-independence resulted in an increase in neutralization sensitivity. While iMac239 was CD4-independent, its CD4-binding site was intact, thus we removed the Aspartic Acid residue at position 385 (analogous to D-368 in HIV-1) to ablate CD4 binding. We found that this novel variant, iMac239-ΔD385, exhibited replication kinetics similar to that of the parental iMac239 strain, and was insensitive to neutralization by soluble CD4. Both CD4-independent strains exhibited an expansion of cellular tropism in vitro with infection of CD4- CD8+ T cells in stimulated rhesus PBMCs.
Next, I present our evaluation of iMac239-ΔD385 pathogenesis and immunogenicity in four rhesus macaques. iMac239-ΔD385 replicated to a high acute viral peak, but was quickly controlled to undetectable levels by the host immune response. iMac239-ΔD385 infection elicited high and sustained neutralizing antibody titers and polyfunctional T cell responses. Strikingly, we observed an alteration in the distribution of infected cells in the lymph node and expansion in the types of cells infected. We tested iMac239-ΔD385 as a live attenuated vaccine against a pathogenic SIVsmE660, and while the number of animals in the study is too small to determine significance we observed a trend toward improved outcomes post challenge, potentially due to a synergistic interaction between iMac239-ΔD385 vaccination and Trim5α alleles.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Microbiology; Virology
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APA (6th Edition):
Swanstrom, A. E. (2015). Dissociating Siv Env and Cd4: Consequenes for Virus and Host. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/2048
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Swanstrom, Adrienne E. “Dissociating Siv Env and Cd4: Consequenes for Virus and Host.” 2015. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/2048.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Swanstrom, Adrienne E. “Dissociating Siv Env and Cd4: Consequenes for Virus and Host.” 2015. Web. 10 Apr 2021.
Vancouver:
Swanstrom AE. Dissociating Siv Env and Cd4: Consequenes for Virus and Host. [Internet] [Thesis]. University of Pennsylvania; 2015. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/2048.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Swanstrom AE. Dissociating Siv Env and Cd4: Consequenes for Virus and Host. [Thesis]. University of Pennsylvania; 2015. Available from: https://repository.upenn.edu/edissertations/2048
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
23.
Hergott, Christopher Bruce.
Microbial Manipulation of Phagocyte Function During Infection and Health.
Degree: 2015, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/1760
► Phagocytic cells comprise a central component of the inflammatory response to pathogens, particularly against extracellular bacteria that proliferate on mucosal surfaces. Mounting evidence suggests that…
(more)
▼ Phagocytic cells comprise a central component of the inflammatory response to pathogens, particularly against extracellular bacteria that proliferate on mucosal surfaces. Mounting evidence suggests that microbes can manipulate phagocyte function dynamically to shape the persistence and efficacy of antibacterial defenses. Successful pathogens often restrain inflammatory responses to evade clearance and promote dissemination within the host. In contrast, commensal bacterial communities have been shown to bolster the functional capacity of phagocytes throughout the body. Despite the critical role of microbe-phagocyte interactions in maintaining health and dictating infection outcome, the mechanisms underlying this influence remain incompletely understood. Here, we examined the impact of pathogenic and commensal microbes on the functions of neutrophils, monocytes, and macrophages, three phagocyte subsets indispensable for antibacterial host defense. Using a mouse model of upper airway infection, we found that the bacterial pathogen Streptococcus pneumoniae (the pneumococcus) exploits molecular mimicry to disarm responding neutrophils. Phosphorylcholine (ChoP) moieties displayed on the exterior of the pneumococcus and within the inflammatory phospholipid platelet-activating factor (PAF) allow the microbe to leverage its ChoP-remodeling enzyme, Pce, to remove PAF from the airway. Neutrophils deprived of PAF signaling fail to eliminate bacteria effectively, allowing the pneumococcus to persist, disseminate systemically, and transmit efficiently between hosts. We found that the pneumococcus also manipulates mononuclear phagocyte responses by stimulating the liberation of macrophage migration inhibitory factor (MIF), a cytokine responsible for retaining macrophages at sites of inflammation. MIF-driven macrophage responses accelerate pneumococcal clearance from the upper airway. However, MIF signaling provokes damaging inflammation and impairs bacterial control during pneumococcal pneumonia, underscoring the tight regulation of phagocyte responses required for effective host defense. Finally, we studied the impact of signals from the intestinal microbiota on systemic phagocyte lifespan, a key component of cellular fitness at homeostasis. We found that a neomycin-sensitive cohort of commensal bacteria augments the survival and circulating lifespan of neutrophils and inflammatory monocytes. This stimulation required signaling through the intracellular peptidoglycan sensor Nod1 and liberation of the pro-inflammatory cytokine IL-17A. Together, these data demonstrate that bacteria modulate phagocyte physiology during infection and health, influencing host readiness and response to pathogenic threats.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Microbiology
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hergott, C. B. (2015). Microbial Manipulation of Phagocyte Function During Infection and Health. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/1760
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Hergott, Christopher Bruce. “Microbial Manipulation of Phagocyte Function During Infection and Health.” 2015. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/1760.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hergott, Christopher Bruce. “Microbial Manipulation of Phagocyte Function During Infection and Health.” 2015. Web. 10 Apr 2021.
Vancouver:
Hergott CB. Microbial Manipulation of Phagocyte Function During Infection and Health. [Internet] [Thesis]. University of Pennsylvania; 2015. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/1760.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hergott CB. Microbial Manipulation of Phagocyte Function During Infection and Health. [Thesis]. University of Pennsylvania; 2015. Available from: https://repository.upenn.edu/edissertations/1760
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
24.
Zou, Tao.
Signals Controlling Regulatory T Cell Differentiation and Homeostasis.
Degree: 2012, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/602
► CD4+Foxp3+ regulatory T cells (Treg)s are essential for the prevention of autoimmunity. Treg lineage commitment requires T cell receptor (TCR) interactions that induce expression of…
(more)
▼ CD4+Foxp3+ regulatory T cells (Treg)s are essential for the prevention of autoimmunity. Treg lineage commitment requires T cell receptor (TCR) interactions that induce expression of foxp3, whose protein product enforces Treg fate. Treg homeostasis is critical for self-tolerance and is achieved through both Treg generation and maintenance. Treg maintenance occurs in part through a process of self-renewing cell division of existing Tregs. This self-renewing Treg division has been shown to be TCR dependent. Despite the crucial role of the TCR in Treg generation and maintenance, neither the specific signaling pathways that control Treg generation nor the nature of the TCR signals required for their division in the periphery are well understood.
Here, we demonstrated that dendritic cells (DC)s coordinate Treg division in vitro. DCs elicit interleukin-2 (IL-2) production from conventional CD4+ T cells (Tconv)s in a major histocompatibility complex class II (MHCII)-dependent fashion. Tconv-derived IL-2 cooperates with contact-dependent signals from DCs to induce Treg division. Contrary to prior studies, we showed that in the presence of exogenous IL-2, Treg division becomes MHCII-independent in vitro. Treg division required only MHCII-independent DC-derived signals and a source of IL-2. Next, we found that peripheral Tregs can divide in the absence of TCR signaling in vivo if exogenous IL-2 receptor (IL-2R) agonists are administered. Furthermore, activation of the IL-2-induced STAT5 pathway is minimally sufficient to support Treg division independent of TCR signaling. These data suggest that depending on the degree of concomitant IL-2 receptor/STAT5 activation, a range of TCR signals can sustain Treg division.
In addition to Treg division, we also investigated the TCR signals that promote Treg development. Our preliminary experiments showed that diacylglycerol (DAG) signaling promotes Treg differentiation. Deletion of diacylglycerol kinase ζ, a negative regulator of this pathway, resulted in augmented DAG signaling and enhanced Treg generation. We hypothesize that DAG signaling enhances NF-κB activation through c-Rel, a transcription factor known to promote Treg differentiation directly. Future studies are necessary to establish the DAG pathway as a link between TCR signaling and Treg differentiation.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA ·
Chicago ·
MLA ·
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APA (6th Edition):
Zou, T. (2012). Signals Controlling Regulatory T Cell Differentiation and Homeostasis. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/602
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Zou, Tao. “Signals Controlling Regulatory T Cell Differentiation and Homeostasis.” 2012. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/602.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Zou, Tao. “Signals Controlling Regulatory T Cell Differentiation and Homeostasis.” 2012. Web. 10 Apr 2021.
Vancouver:
Zou T. Signals Controlling Regulatory T Cell Differentiation and Homeostasis. [Internet] [Thesis]. University of Pennsylvania; 2012. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/602.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Zou T. Signals Controlling Regulatory T Cell Differentiation and Homeostasis. [Thesis]. University of Pennsylvania; 2012. Available from: https://repository.upenn.edu/edissertations/602
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
25.
Zalinger, Zachary Bestor.
Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus.
Degree: 2015, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/2123
► Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection…
(more)
▼ Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection against these organisms, and includes numerous components to defend against a diverse, rapidly evolving pool of pathogens. The immune system is classically divided into two arms, the innate and adaptive systems. The time and metabolic cost of activating the T and B cell responses are considerable, and can also have deleterious side effects if the response is not properly controlled. Therefore, the adaptive immune system is carefully regulated so as to be activated only when necessary. The innate immune system serves to control most pathogens in a more rapid, less energetically expensive manner than the adaptive immune system, and to help regulate subsequent immune responses, guiding and controlling them in order to most efficiently clear pathogens with a minimum of pathological side effects. Among the first elements of the innate system that pathogens encounter are pattern recognition receptors, invariant receptors that detect conserved pathogen associated molecular patterns. Upon recognizing its binding ligand, a pattern recognition receptor will activate a signaling cascade that often triggers production and/or release of one or more pro- inflammatory cytokines. These in turn modulate additional elements of both the innate and adaptive immune responses, and are often critical lynchpins of host defense. Due to this central role in the immune system we investigated the roles of two distinct innate inflammatory pathways, the inflammasome and the MDA5-dependent portion of the type 1 interferon response, during infection with the murine coronavirus mouse hepatitis virus (MHV). Utilizing transgenic mice deficient in Caspase-1 and -11, which catalyze all inflammasome processing, the IL-1 receptor, the IL-18 receptor, or MDA5, we characterize the disease course and subsequent immune response following infection with MHV, a model murine coronavirus. We find that inflammasome signaling is protective during infection, and that much or all of this protection is mediated by IL-18 signaling driving production of interferon gamma by T cells. We also demonstrate that MDA5 signaling controls viral tropism and replication, and that in its absence the host immune response becomes over active, likely leading to lethal pathology. Overall, our studies help define how innate inflammatory pathways can have diverse influences on pathogenesis and the immune response.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Virology
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Zalinger, Z. B. (2015). Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/2123
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Zalinger, Zachary Bestor. “Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus.” 2015. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/2123.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Zalinger, Zachary Bestor. “Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus.” 2015. Web. 10 Apr 2021.
Vancouver:
Zalinger ZB. Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus. [Internet] [Thesis]. University of Pennsylvania; 2015. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/2123.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Zalinger ZB. Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus. [Thesis]. University of Pennsylvania; 2015. Available from: https://repository.upenn.edu/edissertations/2123
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
26.
Ramos Hernández, Natalia M.
The Role of NDFIP1 in T Cell Tolerance.
Degree: 2013, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/686
► Without the ability to suppress its responses, the immune system, instead of being advantageous to the individual, would elicit deleterious consequences. Thus, mechanisms to contain…
(more)
▼ Without the ability to suppress its responses, the immune system, instead of being advantageous to the individual, would elicit deleterious consequences. Thus, mechanisms to contain the activity of immune cells are necessary to prevent immune responses against non-pathogenic antigens and the severe immunopathology that would otherwise result. In T cells, these mechanisms are termed T cell tolerance. T cell tolerance is defined as the collection of T cell intrinsic and extrinsic processes that suppress T cell responses to these non-pathogenic antigens. A breach in T cell tolerance could have fatal results, as evidenced in several autoimmune syndromes. Many of these mechanisms of tolerance occur during T cell development (central T cell tolerance), whereas, others exist in mature T cells (peripheral T cell tolerance). This thesis is focused on the involvement of the adaptor protein Ndfip1 in mechanisms of peripheral T cell tolerance.
Ndfip1 is an adaptor for E3 ubiquitin ligases of the Nedd4 family. In Th2 cells, Ndfip1 is necessary for the degradation of JunB by the Nedd4 family E3 ligase Itch. Consequently, Ndfip1 limits IL-4 expression in Th2 cells. Here we present evidence that Ndfip1 also limits IL-4 expression during the differentiation of inducible Tregs (iTregs), promoting their suppressive program. Thus, by promoting iTreg differentiation, Ndfip1 enforces the proper balance between effector and tolerogenic T cell responses. Ndfip1 also promotes T cell tolerance by regulating T cell activation. Ndfip1 constrains T cell activation by limiting IL-2 mRNA expression. Ndfip1 is part of a negative regulatory system in which factors that induce IL-2 expression downstream of T cell receptor engagement also induce the expression of Ndfip1 to limit the extent of IL-2 production and, thus, control T cell activation. By regulating these two processes, Ndfip1 favors peripheral T cell tolerance and prevents the development of a T cell mediated fatal inflammatory disease.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Ramos Hernández, N. M. (2013). The Role of NDFIP1 in T Cell Tolerance. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/686
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ramos Hernández, Natalia M. “The Role of NDFIP1 in T Cell Tolerance.” 2013. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/686.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ramos Hernández, Natalia M. “The Role of NDFIP1 in T Cell Tolerance.” 2013. Web. 10 Apr 2021.
Vancouver:
Ramos Hernández NM. The Role of NDFIP1 in T Cell Tolerance. [Internet] [Thesis]. University of Pennsylvania; 2013. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/686.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ramos Hernández NM. The Role of NDFIP1 in T Cell Tolerance. [Thesis]. University of Pennsylvania; 2013. Available from: https://repository.upenn.edu/edissertations/686
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
27.
Freund, Jacquelyn Elizabeth.
Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways.
Degree: 2017, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/2290
► Natural killer (NK) cells are lymphocytes of the innate immune system that recognize and eliminate virally infected and transformed cells through their release of cytotoxic…
(more)
▼ Natural killer (NK) cells are lymphocytes of the innate immune system that recognize and eliminate virally infected and transformed cells through their release of cytotoxic granules and production of inflammatory cytokines. The balance of intracellular signals received through NK cell activating and inhibitory receptors dictates these functions and generates target cell specificity during development. Many signaling pathways downstream of activating receptors contribute to these processes, however, what pathways and what signaling proteins contribute to NK cell development and function are not fully understood
While NK cells do not possess an antigen-specific immunoreceptor, they do express a variety of germline-encoded activating and inhibitory receptors. MHC I-binding inhibitory receptors, including those of the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand-specific diversity within the NK cell pool. In this thesis, I demonstrate that signals derived from activating receptors are critical for induction of Ly49 receptors/KIRs during NK cell development; activation signals through SLP-76 increased the probability of the Ly49 bi-directional Pro1 promoter to transcribe in the forward versus the reverse direction, leading to stable Ly49 receptor expression and receptor diversity in mature NK cells.
Not only does activation through SLP-76 impact NK cell development, but downstream signaling pathways also impact NK cell function. Sustained Ca2+ signaling, known as store-operated Ca2+ entry (SOCE), occurs downstream of NK cell activating receptor engagement. CD8+ T cells require SOCE for cytokine production and cytotoxicity; however, less is known about its role in NK cells. In this thesis, I use mice deficient in STIM1/2, which are required for SOCE, to examine the contribution of sustained Ca2+ signaling to NK cell function. Surprisingly, we found that while SOCE is required for NK cell IFNγ production in an NFAT-dependent manner, NK cell degranulation and tumor rejection in vivo remained intact in the absence of SOCE. Our data suggest that mouse NK cells utilize different signaling mechanisms for cytotoxicity compared to other cytotoxic lymphocytes. In summary, NK cell activating receptor signals and downstream signaling pathways contribute greatly to the development and function of NK cells, allowing them to effectively eliminate cancer and virally infected cells.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Freund, J. E. (2017). Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/2290
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Freund, Jacquelyn Elizabeth. “Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways.” 2017. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/2290.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Freund, Jacquelyn Elizabeth. “Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways.” 2017. Web. 10 Apr 2021.
Vancouver:
Freund JE. Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways. [Internet] [Thesis]. University of Pennsylvania; 2017. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/2290.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Freund JE. Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways. [Thesis]. University of Pennsylvania; 2017. Available from: https://repository.upenn.edu/edissertations/2290
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
28.
Glennie, Nelson D.
The Role Of Skin Resident Cd4 T Cells In Cutaneous Leishmaniasis.
Degree: 2017, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/2310
► Cutaneous leishmaniasis is a disease characterized by highly inflammatory, sometimes disfiguring lesions that nonetheless spontaneously resolve, resulting in robust protection against reinfection. It has been…
(more)
▼ Cutaneous leishmaniasis is a disease characterized by highly inflammatory, sometimes disfiguring lesions that nonetheless spontaneously resolve, resulting in robust protection against reinfection. It has been known for decades that a type 1 CD4+ T cell response is critical for both primary parasite control and subsequent protection against reinfection. However, all attempts to artificially reproduce this response have failed, suggesting there may be a gap in our understanding of the memory CD4+ T cells generated by natural infection. In this work, we use a healing mouse model of cutaneous leishmaniasis to explore the role of skin-associated CD4+ T cells in this disease. We demonstrate for the first time that tissue-resident memory (TRM) CD4+ T cells are generated by leishmania infection, are long-lived, and are distributed throughout the skin. We next investigate whether or not these cells contribute to immune protection, and find that leishmania-specific TRM cells can guide the rapid recruitment of circulating T effector cells to the site of challenge, enhancing control of infection. We go on to identify another, novel mechanism of TRM cell-driven protection, in which leishmania-specific TRM cells orchestrate the rapid infiltration and activation of inflammatory monocytes, leading to robust early control of disease even in the absence of circulating T cells. Finally, we explore the requirements for the establishment of TRM cell populations in cutaneous leishmaniasis, with the ultimate goal of understanding how to harness these cells in a potential vaccine.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Glennie, N. D. (2017). The Role Of Skin Resident Cd4 T Cells In Cutaneous Leishmaniasis. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/2310
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Glennie, Nelson D. “The Role Of Skin Resident Cd4 T Cells In Cutaneous Leishmaniasis.” 2017. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/2310.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Glennie, Nelson D. “The Role Of Skin Resident Cd4 T Cells In Cutaneous Leishmaniasis.” 2017. Web. 10 Apr 2021.
Vancouver:
Glennie ND. The Role Of Skin Resident Cd4 T Cells In Cutaneous Leishmaniasis. [Internet] [Thesis]. University of Pennsylvania; 2017. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/2310.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Glennie ND. The Role Of Skin Resident Cd4 T Cells In Cutaneous Leishmaniasis. [Thesis]. University of Pennsylvania; 2017. Available from: https://repository.upenn.edu/edissertations/2310
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
29.
Liu, Mingen.
Metabolic Rewiring Of Macrophages Promotes Anti-Tumor Activity In Pancreatic Cancer.
Degree: 2018, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/3145
► Macrophages abound in the tumor microenvironment of pancreatic cancer and other solid malignancies. Although macrophages typically promote tumorigenesis, they also represent key targets for immunotherapy…
(more)
▼ Macrophages abound in the tumor microenvironment of pancreatic cancer and other solid malignancies. Although macrophages typically promote tumorigenesis, they also represent key targets for immunotherapy approaches, which aim to: 1) deplete macrophages, 2) inhibit their activity, or 3) redirect them toward an anti-tumor role. Redirecting macrophages is commonly described as a phenotypic shift from M2 (anti-inflammatory) to M1 (pro-inflammatory) polarization. However, macrophage phenotypes have grown increasingly diverse and only loosely describe functional roles. Here we examine the anti-tumor functions of macrophages – their ability to engulf and kill tumor cells – and the metabolic dependencies of this process, using a syngeneic and fully immunocompetent tumor model of pancreatic ductal adenocarcinoma (PDAC). In PDAC cells derived from KPC (KrasLSL.G12D/+; Trp53R172H/+; Pdx-Cre) mice, the anti-phagocytic receptor CD47 was knocked out using transient CRISPR-Cas9 expression. CD47 is overexpressed by tumor cells to suppress macrophage anti-tumor activity and escape cancer immunosurveillance. Despite the critical role of CD47, we found that complete loss of CD47 in PDAC cells did not induce macrophage engulfment in vitro, nor did it impact tumor growth in vivo. We hypothesized that macrophages required an activated state, and found that ODN1826, a CpG oligonucleotide, could stimulate macrophages to engulf tumor cells whether they expressed CD47 or not, and without inducing classical M1 or M2 markers. Moreover, CpG treatment of tumor-bearing mice induced potent anti-tumor responses that required macrophages, but not lymphocytes, natural killer cells, or dendritic cells. CpG activation was found to promote oxidative respiration dependent on fatty acid oxidation, along with rewiring of the Krebs cycle through the activity of ATP citrate lyase. Together, these changes represented a hybrid of M1 and M2 metabolisms, and were critical for macrophage engulfment of PDAC cells and anti-tumor activity. Our findings indicate that immune activation of macrophages alter their metabolic state rather than their M1/M2 phenotype to enable them to overcome inhibitory CD47 and carry out anti-tumor activity.
Subjects/Keywords: Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology
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APA (6th Edition):
Liu, M. (2018). Metabolic Rewiring Of Macrophages Promotes Anti-Tumor Activity In Pancreatic Cancer. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/3145
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Liu, Mingen. “Metabolic Rewiring Of Macrophages Promotes Anti-Tumor Activity In Pancreatic Cancer.” 2018. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/3145.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Liu, Mingen. “Metabolic Rewiring Of Macrophages Promotes Anti-Tumor Activity In Pancreatic Cancer.” 2018. Web. 10 Apr 2021.
Vancouver:
Liu M. Metabolic Rewiring Of Macrophages Promotes Anti-Tumor Activity In Pancreatic Cancer. [Internet] [Thesis]. University of Pennsylvania; 2018. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/3145.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Liu M. Metabolic Rewiring Of Macrophages Promotes Anti-Tumor Activity In Pancreatic Cancer. [Thesis]. University of Pennsylvania; 2018. Available from: https://repository.upenn.edu/edissertations/3145
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
30.
Mack, Ethan.
Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function.
Degree: 2018, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/3155
► Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from HSCs into mature effectors remain. The pseudokinase Trib1 is…
(more)
▼ Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from HSCs into mature effectors remain. The pseudokinase Trib1 is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity during eosinophilopoiesis and cellular function of mature eosinophils and neutrophils is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the GMP. Using hematopoietic- and eosinophil-lineage-specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils that retained neutrophilic characteristics and functions, and had increased C/EBPα p42. Using an ex vivo differentiation assay, we identified a previously uncharacterized role for IL-5 in supporting both eosinophil and neutrophil production from the GMP; Trib1 suppressed the neutrophil gene program in lineage-committed eosinophil precursors in response to IL-5 signaling. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. We showed that Trib1 controls eosinophil identity by modulating C/EBPα. Trib1 also controls neutrophil inflammatory function by modulating activation of the AKT, MAPK, and NF-κB pathways Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at multiple distinct stages. Trib1 guides eosinophil lineage commitment from the GMP, suppresses the neutrophil program, and limits neutrophil inflammatory function, together promoting granulocyte terminal identity, lineage fidelity, and homeostasis.
Subjects/Keywords: Allergy and Immunology; Biology; Immunology and Infectious Disease; Medical Immunology
Record Details
Similar Records
Cite
Share »
Record Details
Similar Records
Cite
« Share
❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mack, E. (2018). Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/3155
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Mack, Ethan. “Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function.” 2018. Thesis, University of Pennsylvania. Accessed April 10, 2021.
https://repository.upenn.edu/edissertations/3155.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Mack, Ethan. “Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function.” 2018. Web. 10 Apr 2021.
Vancouver:
Mack E. Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function. [Internet] [Thesis]. University of Pennsylvania; 2018. [cited 2021 Apr 10].
Available from: https://repository.upenn.edu/edissertations/3155.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Mack E. Tribbles Homologue 1 Controls Granulocyte Progenitor Commitment And Terminal Cell Identity And Function. [Thesis]. University of Pennsylvania; 2018. Available from: https://repository.upenn.edu/edissertations/3155
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
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