The inability of the nonobese diabetic class II molecule to form stable peptide complexes does not reflect a failure to interact productively with DM.
Sequence variability in MHC class II molecules plays a major role in genetically determined susceptibility to insulin-dependent diabetes mellitus (IDDM). It is not yet clear whether MHC class II polymorphism allows selective binding of diabetogenic peptides or regulates some key intracellular events associated with class II-restricted Ag presentation. In this study, we have employed gene transfer techniques to analyze the intracellular events that control peptide acquisition by the unique class II molecule expressed by nonobese diabetic mice (I-Ag7). This structurally unique class II molecule fails to demonstrate stable binding to antigenic peptides and fails to undergo the conformational change associated with stable peptide binding to class II molecules. The experiments reported here demonstrate that I-Ag7 can productively associate with two protein cofactors important in class II-restricted Ag presentation, invariant chain (Ii) and DM. DM participates in the removal of the Ii-derived class II-associated Ii chain peptide and the p12 degradation product from the I-Ag7 molecule. In addition, I-Ag7 undergoes a conformational change when DM is expressed within the APC. Finally, DM can mediate accumulation of peptide/class II complexes on the surface of APCs. Collectively, our experiments indicate that the failure of the I-Ag7 molecule to stably bind peptide cannot be attributed to a failure to interact with the DM or Ii glycoproteins.
Peterson
M
M
Department of Pathology, University of Chicago, IL 60637, USA.
Sant
A J
AJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D006681:HLA-D Antigens / Q000378:metabolism* / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011487:Protein Conformation; D012967:Sodium Dodecyl Sulfate
C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D000949:Histocompatibility Antigens Class II; D046911:Macromolecular Substances; D010455:Peptides; D012967:Sodium Dodecyl Sulfate