Germinal center checkpoint restrains anti-insulin B lymphocytes in type 1 diabetes-prone mice

Abstract

Abstract Anti-insulin B lymphocytes (AIBCs) are key drivers of the autoimmune attack in type 1 diabetes (T1D) but their exact functions in T1D pathogenesis, and the point(s) during their development where tolerance is lost, are unknown. In the class-switch-competent anti-insulin B cell receptor transgenic non-obese diabetic (VH125SD.NOD) mice, 1–2% of B lymphocytes are insulin-specific, which accelerates diabetes development despite limited insulin autoantibody (IAA) production. Here we used VH125SD.NOD mice to determine where immune tolerance is lost throughout AIBC class-switch, germinal center entry, and antibody-secreting cell differentiation. We find an increased percentage of AIBCs enter germinal centers relative to non-insulin binding B lymphocytes in the same mice. In addition, an increased percentage of AIBCs are found within the pancreas, class-switch to IgG1, and proliferate relative to non-insulin binding B lymphocytes. We also find that AIBCs are activated in the gut to a greater extent than non-insulin binding B lymphocytes. These data suggest that AIBCs escape anergy and are able to class-switch, enter GCs, and proliferate, but maintain functional silencing preventing spontaneous IAA-production. Moreover, the escape from anergy may occur within the pancreas and/or the gastrointestinal tract. Our data has implications in immunotherapy treatments for T1D, as these GC checkpoints may provide an opportunity for T1D intervention.