Disruption of tolerance by ER stress in type 1 diabetes (BA8P.128)

Abstract

Type 1 diabetes (T1D) is an autoimmune disease, largely mediated by autoreactive T cells, in which islet β cells are destroyed. The events that break peripheral tolerance in individuals genetically predisposed to autoimmunity are poorly understood. Many physiological and environmental triggers associated with T1D, such as viral infection, chemicals, reactive oxygen species, and dynamic glucose sensing, result in endoplasmic reticulum (ER) stress. ER stress increases the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that β cell ER stress generates neo-antigens that activate autoreactive T cells and worsen T1D. Indeed, chemical (Thapsigargin) induction of ER stress in murine islets or insulinomas increased IFNγ secretion from diabetogenic BDC2.5 T cells (28-1500 fold). Chelation of stress-induced calcium (Ca2+) flux reduced this response (27-64%), supporting a role for Ca2+-dependent enzymes such as tissue transglutaminase 2 (Tgase). Tgase activity is higher (18 fold) in β cells under stress, and reduced Tgase expression decreased the BDC2.5 response to β cells under stress (58%). Finally, nonantigenic insulinomas were exposed to normal physiological conditions in vivo. At harvest, these cells had increased ER stress (300 fold), increased Tgase activity (44 fold), and elicited higher BDC2.5 IFNγ responses (22 fold) compared to cultured cells. Thus, β cell ER stress causes formation of neo-antigens that activate autoreactive T cells.