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

ABSTRACT: 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 ? cell endoplasmic reticulum (ER) stress and dysfunction, increasing the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that ? 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? response to these cells was significantly increased compared to non-treated islets. This ? cell ER stress increased activity of the calcium (Ca(2+))-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, ? cell ER stress induced by chemical and physiological triggers leads to ? cell immunogenicity through Ca(2+)-dependent PTM. These findings elucidate a mechanism of how ? cell proteins are modified and become immunogenic, and reveal a novel opportunity for preventing ? cell recognition by autoreactive T cells.

SUBMITTER: Marre ML 

PROVIDER: S-EPMC4958612 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature