The MHC Class II Molecule I-Ag7 Exists in Alternate Conformations That Are Peptide Dependent

Abstract

Insulin-dependent diabetes mellitus is an autoimmune disease that is genetically linked to the HLA class II molecule DQ in humans and to MHC I-Ag7 in nonobese diabetic mice. The I-Ag7 β-chain is unique and contains multiple polymorphisms, at least one of which is shared with DQ alleles linked to insulin-dependent diabetes mellitus. This polymorphism occurs at position 57 in the β-chain, in which aspartic acid is mutated to a serine, a change that results in the loss of an interchain salt bridge between αArg76 and βAsp57 at the periphery of the peptide binding groove. Using mAbs we have identified alternative conformations of I-Ag7 class II molecules. By using an invariant chain construct with various peptides engineered into the class II-associated invariant chain peptide (CLIP) region we have found that formation of these conformations is dependent on the peptide occupying the binding groove. Blocking studies with these Abs indicate that these conformations are present at the cell surface and are capable of interactions with TCRs that result in T cell activation.

Glutamic Acid Decarboxylase-Derived Epitopes with Specific Domains Expand CD4+CD25+ Regulatory T Cells

“…Consistent with this we have shown a difference in structural properties between p524 and p530 using molecular modeling ( Figure 6 and 7 ). This difference may influences the conformation of MHC class II I-A g7 in NOD mice when bound to the corresponding peptide epitopes, as previously reported [48].…”

Presidential Address to The American Association of Immunologists

“…For example, recognition of class I proteins by certain mAbs depends upon the peptide with which the class I is engaged (40 -42). Similar results have been observed for class II and peptides (43,44).…”

The Possibility of B‐Cell‐Dependent T‐Cell Development

“…However, T cells educated in the single-peptide model, are not tolerant to self-MHC bound to another peptide, and react with allogeneic MHC bound to diverse mouse peptides [37]. These results were recently interpreted in the light of structural data showing peptide-induced conformational changes in MHC class I [38][39][40] and in MHC class II molecules [41,42]. Thus, tolerance to the various self-MHC conformations, rather than simply to specific self-peptides, requires T-cell selection on MHC bound to a diverse peptide repertoire.…”