Kai W. Wucherpfennig, MD, PhD
T cells play a critical role in the initiation and progression of autoimmune diseases, and we are investigating the mechanisms of T cell mediated autoimmunity in multiple sclerosis (MS). We have determined crystal structures of two human autoimmune T cell receptors (TCRs) that originated from patients with MS. Transgenic mice that expressed one of these TCRs and the human MHC class II molecule developed spontaneous autoimmunity in the central nervous system, proving that this TCR had pathogenic potential. Both structures showed highly unusual binding topologies that differed substantially from those observed with TCRs specific for infectious agents. The structural differences may be due to distinct selection pressures: during a viral infection there is intense competition between anti-viral T cells favoring expansion of those cells whose TCRs have an optimal fit for their peptide-MHC complex. In contrast, self-reactive T cells that express a TCR with an optimal fit for their self-peptide-MHC complex are most likely to be deleted during T cell development in the thymus. Unusual TCR binding properties may thus provide one of the mechanisms for escape from deletion in the thymus. We have also shown that self-reactive T cells can be activated by microbial peptides that have sufficient structural similarity to the self-peptide, providing a potential mechanism for triggering of autoimmune diseases by infectious agents.