Type 1 Diabetes Depends on CD4-Driven Expression of the Transcriptional Repressor Bcl6

High-affinity islet autoantibodies predict type 1 diabetes in mice and humans and implicate germinal centers (GCs) in disease pathogenesis. T follicular helper (Tfh) cells are increased in individuals with type 1 diabetes and alterations in Tfh-like cells in the peripheral blood predicted individual responses to abatacept. Tfh cells support GC responses and depend on the transcriptional repressor BCL6 for their maturation. Therefore, we hypothesized that CD4-driven deletion of Bcl6 would disrupt essential T- and B-cell interactions in GCs to prevent type 1 diabetes. To test this hypothesis, we generated Bcl6fl/fl-CD4.Cre.NOD mice and found they were completely protected against diabetes. Insulitis severity and tertiary lymphoid structure organization were preserved in the pancreas of Bcl6fl/fl-CD4.Cre.NOD mice, which did not show decreases in CD4+, CD8+, and B-cell numbers in the pancreas and draining lymph nodes, relative to control Bcl6fl/fl.NOD mice. CD4-driven loss of functional BCL6 resulted in significantly reduced GC B-cell and Tfh-cell numbers in the pancreatic lymph nodes and pancreas at late prediabetic intervals. Spontaneous anti-insulin autoantibody was blunted in Bcl6fl/fl-CD4.Cre.NOD mice. These data highlight BCL6 as a novel therapeutic target in type 1 diabetes.

Germinal center B cells and CD4+ T follicular helper cells are implicated in the pathogenesis of type 1 diabetes and depend upon the transcriptional repressor BCL6 for their maturation. This study tests the dependence of type 1 diabetes development on BCL6 expression in CD4+ cells. Data presented here show that CD4-driven loss of Bcl6 blocks germinal center formation, spontaneous insulin autoantibody production, and type 1 diabetes in nonobese diabetic mice, despite normal tertiary lymphoid structure formation in pancreatic islets. This study highlights BCL6 as a potential immunomodulatory target in type 1 diabetes.