Spontaneous T-cell proliferation in the non-obese diabetic mouse to a peptide from the unique class II MHC molecule, I-A(g7), which is also protective against the development of autoimmune diabetes

Aims/hypothesis. Major histocompatibility complex class II molecules presen t antigenic peptides to T-cells and have an important role in T-cell thymic education. The mechanism by which major histocompatibility complex alleles confer a high genetic risk for autoimmune diabetes is not known. One hypot hesis is that during positive thymic selection, the peripheral T-cell reper toire is modelled by major histocompatibility complex-restricted presentati on of self major histocompatibility complex molecule-derived peptides. some of which mimic tissue autoantigens. The sequence similarity between a know n T-cell epitope of glutamic acid decarboxylase-65, 509:VPPSLRTLED and the non-obese diabetic mouse class II major histocompatibility complex molecule I-A(g7) 86:VPTSLRRLEQ is consistent with this. Methods. We measured spontaneous proliferation of peripheral T-cells from n on-obese diabetic mice and other, non-diabetes-prone strains, to the I-A(g7 86-101) and glutamic acid decarboxylase-65(509-524) peptides, binding of t hese peptides to intact I-A(g7) and assessed the effect of tolerance induct ion on diabetes development, by injecting young non-obese diabetic mice wit h high doses of peptide. Results. T-cells from non-obese diabetic, but not other mice strains, spont aneously proliferate to the I-A(g7 86-101) and glutamic acid decarboxylase- 65(509-524) peptides, but not control peptides. Both test peptides bind I-A (g7). Tolerance induction prolongs diabetes-free survival in non-obese diab etic mice when either the I-A(g7 86-101) Or glutamic acid decarboxylase-65( 509-524) peptide, but not control peptide, is used. Conclusion/interpretation. A peptide from the unique class II major histoco mpatibility complex, diabetes-susceptibility molecule, I-A(g7), presented b y I-A(g7) is a target of T-cell responses in diabetes-prone nonobese diabet ic mice and tolerance induction against the peptide offers appreciable prot ection against the development of diabetes.