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Weak Proinsulin Peptide–Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice

¹ Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
² Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri

Corresponding author: Matteo G. Levisetti, mleviset{at}im.wustl.edu

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 β-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 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+ 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 β-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.

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