Unconventional recognition of human regulatory T cells (Tregs) for diabetogenic autoantigens 3490

Abstract Description Type 1 diabetes (T1D), is an autoimmune disease resulting from the progressive destruction of the beta cells in the pancreas. The major genetic determinant in susceptibility/ protection from most autoimmune diseases reside in the major histocompatibility complex (MHC). In T1D, class II MHC alleles such as DR4/DQ8 increases disease risk, while DQ6/DR15, offer protection. Despite the general knowledge that regulatory T cells (Tregs) confers peripheral tolerance in T1D, little is known at present about the mechanism of TCR-peptide-MHC (pMHCs) interactions of Treg cells or their antigenic footprints. We hypothesized that Tregs would adopt unconventional footprints on DR15/DQ6 with different peptide/MHC specificity requirements and would not follow the germline contact rule. Our crystal structure shows the interactions of a human Treg TCR with a MHC bound to GAD65 which does not follow the germline contact rules. Alanine scanning showed key amino acids for Treg TCR signaling. We showed that a human type 1 regulatory T cell recognizing insulin B:10-21 binds to DQ6 in an unconventional way. Binding and mutational studies revealed that the Treg TCR footprint on insulin B:10-21 shifted dramatically towards the peptide C-terminal end, possibly interacting with amino acids outside the peptide binding groove. We conclude that autoimmune Treg TCRs engage pMHC with a distinct unconventional binding topology, and these binding footprints could be exploited in the design of Treg therapeutics Funding Sources This project is supported by NIDDK (R01 DK 137056) and NIAID (RO1 150082). Topic Categories Basic Autoimmunity (BA)