Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes.

Type 1 diabetes results from the destruction of pancreatic beta cells by autoreactive T cells. As an autoantigen with extremely high expression in beta cells, insulin triggers and sustains the autoimmune CD4 and CD8 T cell responses and islet inflammation. We have previously shown that deficiency for insulin-degrading enzyme (IDE), a ubiquitous cytosolic protease with very high affinity for insulin, induces endoplasmic reticulum (ER) stress and proliferation in islet cells and protects non-obese diabetic mice (NOD) from diabetes. Here we wondered whether IDE deficiency affects autoreactive CD8 T cell responses to insulin and thereby immune pathogenesis in NOD mice. We find that NOD harbor fewer diabetogenic T cells and reduced numbers of CD8 T cells recognizing the dominant autoantigen insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Using digestions and cellular antigen presentation assays, we show that generation of the dominant insulin epitope B involves both the proteasome and IDE. IDE deficiency attenuates MHC-I presentation of the immunodominant insulin epitope by beta cells to cognate CD8 T cells. Consequently, islets display reduced susceptibility to autoimmune destruction upon grafting, and to killing by insulin-specific CD8 T cells. Moreover, mice are partly resistant to disease transfer by CD8 T cells specific for insulin but not for IGRP. Thus, IDE has a dual role in beta cells, regulating ER stress and proliferation while at the same time promoting insulin-directed autoreactive CD8 T cell responses.