Identification of endogenous murine leukemia retrovirus antigens attributing to exosome-induced autoimmunity in NOD mice (BA6P.122)

Abstract

Abstract Endogenous autoimmune triggers and antigens are required for initiating the innate and cellular immune responses in the islet of non-obese diabetic (NOD) mice. We found that secreted, nano-sized microvesicles or exosomes are potent inflammatory triggers that, importantly, stimulated autoreactive B and T cells. By performing proteomic analysis, we identified endogenous retrovirus (ERV) proteins, highly homologous to murine leukemia retrovirus (MLV), that are enriched in the exosomes. To study whether these ERV antigens attribute to the autoimmune induction, we produced exosomes lacking the ERV Gag protein and virus-like particles (VLPs), which are nano-sized microvesicles overexpressing Gag and Env proteins. We found that NOD mice spontaneously develop autoantibodies binding to the MLV Env, and also accumulate Env-specific B cells in periphery as compared with diabetes-resistant mice. Autoreactive T cells did not respond to the MLV antigens directly; however, immunization with the exosomes or VLPs induced Gag-specific T cells that inhibited the function of diabetogenic T cell clones in the pancreas. Therefore, ERV antigens may be the targets of autoreactive B and T cells in this T1D mouse model. Consistently, we detected endogenous MLV antigens expressed in the pancreas and by the islet stromal/stem cells in NOD mice. These data support that unique ERV antigens and/or altered formation of exosomes in islet cells may trigger tissue-specific autoimmunity in NOD mice.