Conformation of MHC class II I-A[sup]g7 is sensitive to the P9 anchor amino acid in bound peptide

• Published in: International immunology 2007-09, Vol.19 (9), p.1103
• Main Authors: Gardiner, Amy, Richards, Katherine A, Sant, Andrea J, Arneson, Lynne S
• Format: Article
• Language: English
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxm081

Type I diabetes is a chronic autoimmune disease resulting in the destruction of insulin-producing β cells in the pancreas. In humans, disease incidence is linked to expression of specific MHC class II alleles and in mice type I diabetes is associated with the class II allele I-Ag7 . I-Ag7 contains a polymorphism that is shared by human class II alleles associated with the disease, at position 57 in the β chain, in which aspartic acid is changed to a serine. The P9 pocket in the peptide-binding groove is in part shaped by β57, and therefore the structure of this pocket is modified in I-Ag7 . Using mAbs, we have previously determined that alternative conformations of I-Ag7 form in response to peptide binding. In this study, we have extended these findings by examining how peptides induce I-Ag7 molecules to adopt different conformations. By mutating the amino acid in the P9 position of either class II-associated invariant chain peptide (CLIP) or glutamic acid decarboxylase (GAD) 65 (207-220), we have determined that the chemical nature of the P9 anchor amino acid, either acidic or small hydrophobic, affects the overall conformation of the I-Ag7 class II molecule. T cell hybridomas specific for GAD 65 (207-220) in the context of I-Ag7 were also examined for recognition of I-Ag7 bound to GAD 65 (207-220), in which Glu217 in the P9 position was changed to alanine. We found that although some TCRs were able to recognize both peptides in the context of I-Ag7 , and thus both class II conformations, approximately one-third of the T cells tested were not able to recognize the alternate class II conformation formed with the mutated peptide. These results indicate that the I-Ag7 conformations may affect functional activation of T cells, and thus may play a role in autoimmunity.