Weak proinsulin peptide-major histocompatibility complexes are targeted in autoimmune diabetes in mice

OBJECTIVE-Weak major histocompatibility complex (MHC) binding of self-peptides has been proposed as a mechanism that may contribute to autoimmunity by allowing for escape of autoreactive T-cells from the thymus. We examined the relationship between the MHC-binding characteristics of a P-cell antigen epitope and T-cell autoreactivity in a model of autoimmune diabetes. RESEARCH DESIGN AND METHODS-The binding of a proinsulin epitope, proinsulin-1(47-64) (PI-1[47-64]), to the MHC class 11 molecules I-A(g7) and I-A(k) was measured using purified class H molecules. T-cell reactivity to the proinsulin epitope was examined in I-A(g7+) and I-A(k), mice. RESULTS-C-peptide epitopes bound very weakly to I-A(g7) molecules. However, C-peptide-reactive T-cells were induced after immunization in I-A(g7)-bearing mice (NOD and B6.g7) but not in I-A(k)-bearing mice (B10.BR and NOD.h4). T-cells reactive with the PI-1(47-64) peptide were found spontaneously in the peripancreatic lymph nodes of pre-diabetic NOD mice. These T-cells were activated by freshly isolated P-cells in the presence of antigen-presenting cells and caused diabetes when transferred into NOD.scid mice. CONCLUSIONS-These data demonstrate an inverse relationship between self-peptide-MHC binding and T-cell autoreactivity for the PI-1(47-64) epitope in autoimmune diabetes.