Dissecting the role of HB-EGF in the shaping of CD4+ T cell immune responses

CD4+ T cells critically contribute to host protection against infections but can also participate in the development of autoimmune diseases. Correct differentiation of naïve CD4+ T cells into effector subtypes is essential to ensure regulation of immune responses and prevention of autoimmunity. Nonetheless, the underlying mechanisms governing this process remain only partially understood. Upon activation, human and mouse CD4+ T cells both express the Epidermal Growth Factor receptor (EGFR) and its high affinity ligand HB-EGF, a growth factor known to strongly activate the MAP kinase (MAPK) signalling pathway and potentially interfere with intracellular TGFb signalling. Contribution of HB-EGF-derived signalling in T cells remains poorly studied, therefore the aim of my thesis was to further elucidate the role of HB-EGF in CD4+ T cell differentiation and function. Firstly, I found that HB-EGF sustained EGFR expression on activated murine CD4+ T cells, and that the strength of T cell activation influenced HB-EGF expression. HB-EGF was also found to enhance Interleukin-2 (IL-2) expression upon activation. As IL-2 is required for the clonal expansion of T cells, I used a model of Listeria monocytogenes infection to measure antigen-specific CD4+ T cell responses in HB-EGF-deficient mice. I found that in these mice, antigen-specific CD4+ T cells appeared to have a lower affinity for their cognate antigen compared to wild type C57BL/6 mice. In addition, they possessed a more diverse T cell repertoire with less skewing towards dominant CD4+ T cell clones. These findings suggest an involvement of HB-EGF in the shaping of epitope-specific CD4+ T cell responses. Next, I showed through in vitro T cell differentiation that HB-EGF expression reduced the capacity of naïve CD4+ T cells to differentiate into T helper 17 (Th17) effector cells, potentially, by enhancing IL-2 expression and thereby inhibiting TGFb-mediated signalling. Finally, since Th17 cells are implicated in the development of several autoimmune diseases, I utilised mouse models of EAE and T cell-induced colitis to demonstrate that mice with a T cell-specific deficiency of HB-EGF expression displayed enhanced in vivo differentiation of CD4+ T cells into Th17 effector cells and, consequently, induced the rapid onset of autoimmune diseases. Taken together, the work presented in this thesis suggests a novel mechanism by which T cell-derived HB-EGF shapes antigen-specific CD4+ T cell responses and constrains Th17 differentiation, thereby preventing the development of autoimmune diseases