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

Authors

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.

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Aug 2026.

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