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

Currently approved immunotherapies for type 1 diabetes (T1D) broadly target T cells and delay, but do not fully prevent, diabetes development, highlighting the need for more selective targets. Here, we show that T cell loss of the key germinal center protein, BCL6 prevents diabetes, despite the continued presence of anti-insulin B cells. This protection was associated with reduced anti-insulin B cell activation and proliferation. ΔBCL6 adoptively transferred CD4+ T cells showed reduced activation, relative to BCL6 sufficiency. Anti-insulin B cells primarily existed in extrafollicular niches and skewed toward phenotypically defined atypical and atypical memory B cell subsets in pancreas and pancreatic lymph nodes, which was reduced by T cell loss of BCL6. This work implicates CD4+ T cells in licensing extrafollicular insulin-binding B cells, a process which is restrained by T cell BCL6 deficiency. Overall, these findings support BCL6 inhibition as a promising T1D immunotherapy.