Molecular mechanisms of T cell receptor recognition and triggering
T cells play a fundamental role in the initiation of immune responses, and our lab seeks to understand the mechanisms of T cell recognition and function. We examine the mechanisms of T cell receptor recognition and T cell receptor (TCR) triggering using molecular, structural and imaging approaches. We have recently shown that the tyrosine-based activation motif (ITAM) of the CD3ε chain of the TCR is lipid-bound in non-activated T cells and that the two critical tyrosines are deeply inserted into the hydrophobic interior of the lipid bilayer. Such lipid binding protects the tyrosines from phosphorylation by Src kinanses. We are now investigating how TCR triggering renders these tyrosines accessible for phosphorylation. These mechanisms may be relevant for many other receptors in the immune systems that also signal through ITAMs.

Mechanisms for the development of T cell mediated autoimmune diseases
We also study the causes of T cell mediated autoimmune diseases, in particular multiple sclerosis and type 1 diabetes, in which self-reactive T cells escape negative selection in the thymus. We have found that T cell receptors do not recognize a single MHC/peptide ligand but that they can actually be activated by a number of different peptide ligands with limited sequence similarity. This finding explains why many autoimmune diseases appear to be triggered by infectious agents.

We are exploring the mechanisms of T cell mediated autoimmunity using molecular, structural and cellular approaches and are working on novel approaches for the treatment of these diseases based on a molecular understanding of disease pathogenesis.