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.