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

Departments of Medicine ¹
Pathology and Immunology² Washington University School of Medicine, Saint Louis, MO 63110

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.

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