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 DRB1*0406 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 DRB1*0406 molecule. YN5-32 responded better to M12p54-68 presented by allogeneic DRB1*0403 with a single Tyr-substitution at DR beta 37-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 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.
Chen
Y Z
YZ
Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
Matsushita
S
S
Nishimura
Y
Y
D000483:Alleles; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics*; D017951:Antigen Presentation / Q000235:genetics; D002999:Clone Cells; D000939:Epitopes / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D007519:Isoantigens / Q000235:genetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology*; D011110:Polymorphism, Genetic; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D000596:Amino Acids; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007519:Isoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell