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Karolinska Institute

1. Salam, Sadia. Natural killer cell education under conditions of perturbed sensing of MHC : studies in MHC-I mosaic and chimaeric mice .

Degree: 2017, Karolinska Institute

Natural killer (NK) cells are innate lymphocytes that play a role in infections, tumours and transplantation. Their activating and inhibitory receptors sense cell surface ligands on potential target cells. Increased levels of stress induced activating ligands and decreased levels of inhibitory MHC class I (MHC-I) ligands cause activation of NK cells. NK cells are “educated” to tolerate self, and the “rheostat model” proposes that this is a reversible and quantitative process, where the degree of responsiveness acquired by each NK cell is proportional to the amount of perceived inhibitory MHC-I signals. Assuming that the NK cell integrates MHC-I input over multiple cell encounters, education may also depend on the ratio between cells with and without a critical MHC- I ligand, e.g. in chimaerism after haematopoietic transplantation. This thesis addressed how NK cell education is affected by perturbed sensing of MHC-I, and how the process is influenced quantitatively by the frequency of cells with a given MHC-I ligand. “Allele specific” as well as “general” missing self reactivity (targets lacking one or all host MHC-I molecules respectively), against normal and tumour target cells, was analysed. The DL6 mouse strain presents a mosaic expression of an MHC-I transgene such that each cell either expresses it (Dd+) or not (Dd-). To test NK cell killing in vivo of two different targets in the presence of a control cell population in these mice, one aim was to develop an assay to measure rejection of three fluorochrome labelled targets in parallel. Using this assay, all mosaic DL6 mice were completely tolerant towards normal Dd- spleen cells (“allele specific” missing self), even if they had a relatively high proportion of Dd+ vs. Dd- cells. There were varying degrees of impaired reactivity in the mosaic mice upon challenge with MHC-I defective spleen cells (“general” missing self), with a moderate inverse correlation between the number of host Dd+ cells and the survival of these target cells. Tolerance towards Dd- RMA tumour cells representing “allele specific” missing self was not complete; partial rejection was observed in many DL6 mice. There was a weak inverse correlation between the number of Dd+ cells and the survival of these target cells; in particular, there was an efficient rejection in all mice with >83% Dd+ cells. The frequency of Dd+ cells did not influence rejection of MHC-I deficient RMA-S lymphoma cells; all DL6 mice rejected these cells efficiently. In chimaera studies where Dd+ bone marrow was used to reconstitute mosaic DL6 mice, there was again complete tolerance towards normal Dd- spleen cells, indicating that a fraction of ligand deficient nonhaematopoietic cells is sufficient to induce tolerance to normal cells of this phenotype. Again, the results differed when tumour cells were used; there was significant (but reduced) capacity for “allele specific” missing self rejection in these chimaeras. In the reverse setting, mixed bone marrow chimaeras were constructed in…

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APA (6th Edition):

Salam, S. (2017). Natural killer cell education under conditions of perturbed sensing of MHC : studies in MHC-I mosaic and chimaeric mice . (Thesis). Karolinska Institute. Retrieved from http://hdl.handle.net/10616/45922

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):

Salam, Sadia. “Natural killer cell education under conditions of perturbed sensing of MHC : studies in MHC-I mosaic and chimaeric mice .” 2017. Thesis, Karolinska Institute. Accessed October 24, 2017. http://hdl.handle.net/10616/45922.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Salam, Sadia. “Natural killer cell education under conditions of perturbed sensing of MHC : studies in MHC-I mosaic and chimaeric mice .” 2017. Web. 24 Oct 2017.

Vancouver:

Salam S. Natural killer cell education under conditions of perturbed sensing of MHC : studies in MHC-I mosaic and chimaeric mice . [Internet] [Thesis]. Karolinska Institute; 2017. [cited 2017 Oct 24]. Available from: http://hdl.handle.net/10616/45922.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Salam S. Natural killer cell education under conditions of perturbed sensing of MHC : studies in MHC-I mosaic and chimaeric mice . [Thesis]. Karolinska Institute; 2017. Available from: http://hdl.handle.net/10616/45922

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.