BCL6 in T cells promotes type 1 diabetes by redirecting fates of insulin-autoreactive B lymphocytes
Year: 2026
Type: article
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
Source: iScience
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Funders: Vanderbilt University, Indiana University, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Division of Diabetes, Endocrinology, and Metabolic Diseases, JDRF
Awards: G1339403715, G1396180089, G2268269956, G2393314170, G2566790412, G3269002440, G3726302789, G3756376927, Medical Scientist Training Program, G4225702427, G4513176822, G4570253477, G5497649447, G7642566612, G9000064184, G9000076948, G9000089795, Molecular and Cellular Basis for Digestive Diseases, Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease, Evolution of B Lymphocyte Insulin Autoantigen Recognition in Type 1 Diabetes, Interdisciplinary Training in Rheumatic Diseases, NRSA Training Core, Vanderbilt Diabetes Research Center, Identifying Mechanisms of Tfh/Germinal Center B cell Pathogenicity in Type 1 Diabetes
OpenAlex ID: W4413800699