A single residue polymorphism at DR beta 37 affects recognition of peptides by T cells.

Single amino acid polymorphism at residue 37 of the HLA-DR beta chain (DR beta 37) between DRB10406 and 0403 markedly influences susceptibility to the insulin autoimmune syndrome. We investigated the effects of DR beta 37 polymorphism regarding recognition of nonself peptides by a T-cell clone, YN5-32, specific to a streptococcal peptide (M12p54-68) presented by the DRB10406 molecule. YN5-32 responded better to M12p54-68 presented by allogeneic DRB10403 with a single Tyr-substitution at DR beta 37-Ser of the DRB10406 molecule. One hundred and fifty-four peptides carrying single residue substitutions at each of the core residues 57-65 of M12p54-68, were tested for full agonistic and TCR antagonistic activities. Forty-six peptides showed full agonism, 34 analogues exhibited TCR antagonism, and 45 analogues exhibited neither full agonism nor TCR antagonism, irrespective of the presenting molecules (DRB1*0406 or 0403). On the other hand, 29 analogue peptides substituted at each of residues 57-63 of M12p54-68 were recognized differently by YN5-32, depending on the presenting molecules. These observations indicate that 1) single amino acid polymorphism (Ser-Tyr) at the DR beta 37 residue induced a conformational change distinguished by TCR in some but not all peptides; and 2) these conformational changes were observed even in analogue peptides carrying single residue substitutions at residues far from a putative DR beta 37 contact site. These findings provide further evidence for altered human T-cell responses induced by TCR ligands with minor modifications.