Clark, L. M. | bioRxiv Science

bioRxiv2026

SAP loss limits anti-insulin atypical B cell activation and pro-inflammatory CD8 T cells despite preserved Tfh responses to protect against type 1 diabetes

SLAM-associated protein (SAP) is required for T follicular helper (Tfh)-B cell interactions that underlie germinal center formation, but it is unclear if SAP governs islet-reactive CD4+ T cell-B cell interactions and downstream pro-inflammatory CD8+ T cell destruction of islets in type 1 diabetes (T1D). To address this question, we utilized the VH125SD.NOD mouse model, whereby 1-3% of all B cells bind insulin. Germline SAP loss in this model led to reduced T1D incidence and impaired germinal center B cell formation, yet did not alter T follicular helper cell formation or phenotype. SAP loss reduced pro-inflammatory and activated insulin-autoreactive B-T interactions and limited anti-insulin B cell proliferation, activation, and upregulation of co-stimulatory molecules otherwise enhanced in the pancreas. Anti-insulin extrafollicular antibody and memory responses following immunization were preserved in VH125SD.SAP-/-.NOD mice, but activated atypical anti-insulin B cell responses were reduced. Ultimately, SAP loss led to reduced pro-inflammatory CD8+ T cell formation and islet-reactive progenitor exhausted CD8+ T cells in pancreata. These data highlight the essential role of SAP in mediating proinflammatory, anti-insulin B-T interactions to support T1D. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/741363v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1971e3borg.highwire.dtl.DTLVardef@41d72eorg.highwire.dtl.DTLVardef@963004org.highwire.dtl.DTLVardef@2a76b5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

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

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 VH125SD.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{Delta}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 VH125SD.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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/671997v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@bf0daforg.highwire.dtl.DTLVardef@11b95fdorg.highwire.dtl.DTLVardef@141ccaorg.highwire.dtl.DTLVardef@6e4100_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗