A Single Residue Polymorphism at DRβ 37 Affects Recognition of Peptides by T Cells

Abstract

Single amino acid polymorphism at resi-due 37 of the HLA-DRβ chain (DRβ 37) between DRB1∗0406 and 0403 markedly influences susceptibility to the insulin autoimmune syndrome. We investigated the effects of DRβ 37 polymorphism regarding recognition of nonself peptides by a T-cell clone, YN5-32, specific to a streptococcal peptide (M12p54-68) presented by the DRB1∗0406 molecule. YN5-32 responded better to M12p54-68 presented by allogeneic DRB1∗0403 with a single Tyr-substitution at DRβ37-Ser of the DRB1∗0406 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 DRβ 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 DRβ37 contact site. These findings provide further evidence for altered human T-cell responses induced by TCR ligands with minor modifications.