Weak proinsulin peptide-MHC complexes are targeted in autoimmune diabetes in mice

Abstract

Objective Weak 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 beta cell antigen epitope and T cell autoreactivity in a model of autoimmune diabetes.

Research Design and Method The binding of a proinsulin epitope, PI-1(47-64), to the MHC class II molecules I-A^g7 and I-A^k was measured using purified class II molecules. T cell reactivity to the proinsulin epitope was examined in I-A^g7 and I-A^k positive mice.

Results C-peptide epitopes bound very weakly to I-A^g7 molecules. However, C-peptide reactive T cells were induced following 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 proinsulin-1(47-64) peptide were found spontaneously in the peri-pancreatic lymph nodes of prediabetic NOD mice. These T cells were activated by freshly isolated beta cells in the presence of antigen presenting cells (APC) 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 proinsulin-1(47-64) epitope in autoimmune diabetes.