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 type 1 diabetes pathogenesis. T follicular helper (Tfh) cells are increased in type 1 diabetic individuals 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. We therefore hypothesized that CD4-driven deletion of Bcl6 would disrupt essential T-B lymphocyte interactions in GCs to prevent type 1 diabetes. To test this hypothesis, we generated Bcl6^fl/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 Bcl6^fl/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 Bcl6^fl/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 pre-diabetic intervals. Spontaneous anti-insulin autoantibody was blunted in Bcl6^fl/fl-CD4.Cre.NOD mice. These data highlight BCL6 as a novel therapeutic target in type 1 diabetes.