Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic cell destruction induced by islet reactive T cells that have escaped central tolerance. Many physiological and environmental triggers associated with T1D result in 13 cell endoplasmic reticulum (ER) stress and dysfunction, increasing the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that 13 cell ER stress induced by environmental and physiological conditions generates abnormally modified proteins for the T1D autoimmune response. To test this hypothesis we exposed the murine CD4(+) diabetogenic BDC2.5 T cell clone to murine islets in which ER stress had been induced chemically (Thapsigargin). The BDC2.5 T cell IFN gamma response to these cells was significantly increased compared to non-treated islets. This beta cell ER stress increased activity of the calcium (Ca2+)-dependent PTM enzyme tissue transglutaminase 2 (Tgase2), which was necessary for full stress -dependent immunogenicity. Indeed, BDC2.5 T cells responded more strongly to their antigen after its modification by Tgase2. Finally, exposure of non-antigenic murine insulinomas to chemical ER stress in vitro or physiological ER stress in vivo caused increased ER stress and Tgase2 activity, culminating in higher BDC2.5 responses. Thus, 13 cell ER stress induced by chemical and physiological triggers leads to beta cell immunogenicity through Ca2+-dependent PTM. These findings elucidate a mechanism of how beta cell proteins are modified and become immunogenic, and reveal a novel opportunity for preventing beta cell recognition by autoreactive T cells. (C) 2016 Elsevier Ltd. All rights reserved.