Initiation, dynamic control and long-term consequences of T cell antigen receptor signalling: understanding etiology and therapy of immune diseases

T cells orchestrate adaptation to pathogenic, symbiotic and commensal microbiota and dominant tolerance. These fitness-ensuring roles rely on complex signalling mechanisms that steer the fate of T cells from inception to disposal. Signals from the T cell antigen receptor (TCR) recognition of a panoply of pMHC ligands during thymic development, peripheral circulation, mucosa residency and antigen encounter are translated into short- and long-term functional outcomes. I aim to build on our original findings in this key area of T cell biology. Having uncovered the molecular basis for allosteric TCR signalling, I will map the structures that sense ligand binding and investigate the role of TCR-specific lipid shell/nanodomains in signal transduction. I will also analyse how TCR signals are processed by the THEMIS:SHP complex to balance cell survival and death. Finally, I will expand on our recent finding that virtually all major transcription factors required for CD4-T cell fate decisions, including Tbet, Foxp3 and RUNX, are modified by Protein Arginine Methyltransferases (PRMTs) to determine whether these post-translational “marks” impart phenotypic stability. These studies will elucidate control mechanisms in T cell biology and beyond and contribute to the development of novel strategies of immunotherapy and immune disease prevention.