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bioRxiv · 10.64898/2026.07.29.741363

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

Clark, L. M.·McNitt, D. H.·McAninch, J. C.·Bass, L. E.·Padgett, M. L.·Moreno, A. F.·Brannon, C. T.·Nichols, C. M.·Stier, M. T.·Bonami, R. H.
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Abstract

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

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Clark, L. M., McNitt, D. H., McAninch, J. C., Bass, L. E., Padgett, M. L., Moreno, A. F., Brannon, C. T., Nichols, C. M., Stier, M. T., Bonami, R. H.. 2026-08-02. 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. https://doi.org/10.64898/2026.07.29.741363

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