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Universitat de Barcelona

1. Rovira Clavé, Xavier. Funció de SDC2 i ERK5 en la regulació de l'expressió en la superfície cel·lular del complex TCR/CD3 i LFA-1.

Degree: Departament de Biologia Cel·lular, Fisiologia i Immunologia, 2016, Universitat de Barcelona

Regulation of the TCR/CD3 complex and integrin LFA-1 expression at the cell surface is critical to proper T cell adhesion and activation. T cells express the heparan sulphate proteoglycans syndecan-2 (SDC2) and syndecan-4 (SDC4). SDC4 plays a T cell inhibitory role, however, the function of SDC2 in T cells is unknown. In an attempt to examine this function, SDC2 was expressed constitutively in Jurkat T cells. Here, we show the down-regulation of LFA-1 and inhibition of adhesion of Jurkat T cells transfected with SDC2. The PDZ-binding domain in the cytoplasmic region of SDC2 was necessary to block the LFA-1 high-affinity conformation, and to reduce cellular adhesion. A second cytoplasmic motif comprising tyrosines 179 and 191, and serines 187 and 188 contributed also to reduce LFA-1 function and cellular adhesion. Moreover, the expression of SDC2 decreased the surface levels of TCR/CD3 complex, concomitant with intracellular retention of CD3e and partial degradation of the TCRz chain. The lower TCR/CD3 surface levels caused by SDC2 led to reduced TCR/CD3 responsiveness. We also provide evidence that the MAPK ERK5 regulates the surface expression of the TCR/CD3 complex by controlling the degradation of the TCRz chain and the recovery of the complex after anti-CD3e stimulation. ERK5 knockdown led to TCR/CD3 up-regulation at the cell surface and increased amounts of the TCRz chain. Inhibition of the MEK5-dependent phosphorylation status of the kinase domain of ERK5 in human T CD4+ cells reduced TCRz ubiquitination and degradation, limiting TCR/CD3 down-regulation in anti-CD3e-stimulated cells. Moreover, TCR/CD3 recovery at the cell surface, after anti-CD3e treatment, is impaired by ERK5 knockdown or pharmacological inhibition of autophosphorylation in the ERK5 C-terminal region. ERK5 loss in thymocytes augmented cellular TCRz and increased cell surface levels of TCR/CD3 on CD4+CD8+ thymocytes. This correlated with enhanced generation of CD4+CD8-CD25+ thymocytes. In conclusion, our results propose SDC2 as an inhibitor of T cell adhesion and activation, due to its regulation of TCR/CD3 complex expression at the cell surface and LFA-1 integrin activation. Moreover, our study identifies ERK5 as a novel kinase that modulates TCR/CD3 expression at the cell surface in mouse and human T cells. Advisors/Committee Members: [email protected] (authoremail), false (authoremailshow), Espel Masferrer, Enric (director), Reina del Pozo, Manuel (director), true (authorsendemail).

Subjects/Keywords: Limfòcits; Linfocitos; Lymphocytes; Cèl·lules T; Células T; T cells; Glicoproteïnes; Glucoproteínas; Glycoproteins; Ciències Experimentals i Matemàtiques; 576

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APA (6th Edition):

Rovira Clavé, X. (2016). Funció de SDC2 i ERK5 en la regulació de l'expressió en la superfície cel·lular del complex TCR/CD3 i LFA-1. (Thesis). Universitat de Barcelona. Retrieved from http://hdl.handle.net/10803/398129

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):

Rovira Clavé, Xavier. “Funció de SDC2 i ERK5 en la regulació de l'expressió en la superfície cel·lular del complex TCR/CD3 i LFA-1.” 2016. Thesis, Universitat de Barcelona. Accessed August 24, 2019. http://hdl.handle.net/10803/398129.

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

MLA Handbook (7th Edition):

Rovira Clavé, Xavier. “Funció de SDC2 i ERK5 en la regulació de l'expressió en la superfície cel·lular del complex TCR/CD3 i LFA-1.” 2016. Web. 24 Aug 2019.

Vancouver:

Rovira Clavé X. Funció de SDC2 i ERK5 en la regulació de l'expressió en la superfície cel·lular del complex TCR/CD3 i LFA-1. [Internet] [Thesis]. Universitat de Barcelona; 2016. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10803/398129.

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

Council of Science Editors:

Rovira Clavé X. Funció de SDC2 i ERK5 en la regulació de l'expressió en la superfície cel·lular del complex TCR/CD3 i LFA-1. [Thesis]. Universitat de Barcelona; 2016. Available from: http://hdl.handle.net/10803/398129

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

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