Disruption of tolerance by ER stress in type 1 diabetes (BA4P.131)

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Abstract Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive T cells target and destroy islet β cells. The events that break peripheral tolerance in patients genetically predisposed to autoimmunity are poorly understood. Many physiological and environmental triggers associated with T1D cause endoplasmic reticulum (ER) stress, which may increase abnormal protein post-translational modification (PTM). We hypothesized that β cell ER stress generates neo-antigens that activate autoreactive T cells in T1D. Chemical (Thapsigargin) induction of ER stress in murine islets or insulinomas increased their recognition by diabetogenic BDC2.5 T cells (28-1500 fold) through activation of the PTM enzyme tissue transglutaminase 2 (Tgase; 18 fold). Indeed, reduced Tgase expression decreased stress-induced immunogenicity (58%). Also, physiological conditions in vivo increased ER stress (300 fold) and Tgase activity (44 fold) in primary islets and transplanted insulinomas, increasing BDC2.5 IFNγ responses (22 fold). Thus, ER stress leads to PTM-dependent murine β cell immunogenicity. We are currently translating these findings to a human T1D model. Preliminary data confirm that ER stress in human β cells significantly increased IFNγ secretion by T cells isolated from T1D patients that recognize Tgase-modified β cell antigens (24-360 fold). Thus, Tgase-dependent PTM may also cause immunogenicity in human β cells, demonstrating the relevance of our murine studies to human disease.