Searching for natural Treg peptide-MHC ligands by engineering increased affinity/avidity Treg TCRs. (IRC5P.621)

Abstract

Abstract Natural Tregs (nTregs) are produced in the thymus by selection to self peptide-MHC (spMHC) complexes. There is abundant data in the literature that suggests nTreg TCRs are higher affinity for self than conventional T cells and respond to spMHC in the periphery. To date, no nTreg ligands have been found, in part, possibly because nTregs may have TCR affinities that fall somewhere between the affinties required for positive and negative selection in the thymus for conventional T cells. This implies that although nTreg TCRs may be higher affinity for self, this affinity may still be lower than a conventional T cell TCR has for it's immunological antigen. To overcome this, we have developed a way to increase the affinity for some nTreg TCRs for pMHC while still mainting peptide specificity. Using these higher affinity nTreg TCRs, we can scan peptide-MHC libraries in order to find peptide mimitopes which may lead us to the actual self-peptides which are able stimulate specific nTregs.