BCL6 in T cells promotes type 1 diabetes by redirecting fates of insulin-autoreactive B lymphocytes

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Abstract Currently approved type 1 diabetes (T1D) immunotherapies broadly target T cells and delay but do not fully prevent diabetes development, highlighting the need for more selective targets. Anti-insulin germinal center B cells are uniquely able to present pathogenic insulin epitopes and drive anti-insulin T cells to adopt a T follicular helper fate. T cell expression of BCL6, a key transcriptional repressor in the germinal center response, is essential for spontaneous diabetes in non-obese diabetic (NOD) mice. However, the impact of T cells on pro-pathogenic anti-insulin B cell activity is still poorly understood. Here, we show that VH125 SD .NOD mice with T cell loss of BCL6 still produce peripheral anti-insulin B cells yet are protected against diabetes (relative to Bcl6 -sufficient controls). This protection was associated with reduced activation, proliferation, germinal center differentiation, and pancreatic infiltration of insulin-binding B cells. Minimally supervised analysis revealed insulin-binding B cells skew towards atypical memory B cell subsets specifically in pancreas and pancreatic lymph nodes, which was reduced by Bcl6 Δ CD4 loss. Overall, this work suggests BCL6-expressing T cells are pivotal to license pathogenic insulin-binding B cells. Our findings support BCL6 inhibition as a promising T1D immunotherapy, even after insulin autoimmunity is established in the B cell repertoire. Article Highlights - Loss of floxed Bcl6 via Cd4 -Cre protects against type 1 diabetes even when an insulin-skewed B cell repertoire is present - BCL6 loss in T cells reduces anti-insulin B cell upregulation of T cell co-stimulatory molecules, proliferation, and IgG class switching in pancreas and pancreatic lymph nodes in VH125 SD .NOD mice - Anti-insulin B cells skew towards atypical and atypical memory B cell phenotypes compared to non-insulin binding B cells in pancreas and pancreatic lymph nodes, only some of which are reduced by T cell loss of Bcl6 - This study highlights the translational potential of targeting BCL6, even after the establishment of insulin-reactive B cells, in line with typical intervention points for at-risk individuals Graphical Abstract

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