Our overarching question is: how do mutations in genes involved in the activation and regulation of T cell responses contribute to regulation of immune homeostasis and at what point do perturbations in homeostatic mechanisms tip over into autoimmunity? Activation and termination of immune responses are balanced through cross-talk between tyrosine kinases and phosphatases immediately downstream of the T cell receptor (TCR). Changes in expression and point mutations in these influential kinases and phosphatases have been linked to autoimmunity; how do these mutations perturb homeostasis and result in a failure of regulation? At what point do perturbations in the homeostatic balance of the immune system tip into immunopathology and autoimmunity? What are the mechanisms that underlie these processes?

In order to answer these questions we use genetically altered mouse models e.g. transgenics, knockouts, knockins and inducible expression of genes or combinations of genes; we are using Cripr/Cas technology to introduce equivalent mutations into primary human and mouse T cells to study their consequences; we study activation and regulation of T cell responses in vivo and in vitro; we look at T cell signalling and we perform transcriptional and proteomics analysis to try and understand the mechanistic basis of the phenotypes we observe.