Mechanisms and consequences of T cell antigen receptor signalling for normal immune homeostasis and the development of autoimmune disease

T cells are essential components of the adaptive immune response and prime drivers of autoimmune diseases, yet we lack in depth understand of how responses are initiated and terminated, and even less understanding of the precipitating events that result in disease. Activation and termination of immune responses are balanced through cross-talk between tyrosine kinases and phosphatases immediately downstream of the T cell receptor. We will use genetically altered (GA) mice to manipulate early signals and address the contributions of the Src-family kinases, Lck and Fyn, and the phosphatase, PTPN22, to normal and abnormal activation of T cells. Genome wide association studies have identified PTPN22 as a major autoimmune susceptibility allele and its regulation of the Src-family kinases, amongst other substrates, influences T cell homeostasis. We will perform in vivo studies to follow the behavior of T cell populations from GA mice following antigenic challenge and underpin these with in vitro studies of the biochemical and biological processes that regulate T cell activation. Together these investigations will interrogate the contributions of: abnormal activation of T cells, cell intrinsic failures to terminate a normal response, and the failure to externally regulate a normal response, as drivers of autoimmunity.