Abstract
Signaling lymphocytic activation molecule-associated protein (SAP), a critical intracellular signaling molecule for T-B lymphocyte interactions, drives T follicular helper (Tfh) cell development in germinal centers (GCs). High-affinity islet autoantibodies predict type 1 diabetes (T1D) but do not cause β cell destruction. This paradox intimates Tfh cells as key pathologic effectors, consistent with an observed Tfh signature in T1D. To understand how fully developed Tfh (GC Tfh) contribute to different autoimmune processes, we investigated the role of SAP in T1D and autoantibody-mediated arthritis. Whereas spontaneous arthritis depended on SAP in the autoantibody-mediated K/BxN model, organized insulitis and diabetes onset were unabated, despite a blocked anti-insulin vaccine response in SAP-deficient NOD mice. GC Tfh and GC B cell development were blocked by loss of SAP in K/BxN mice. In contrast, although GC B cell formation was markedly reduced in SAP-deficient NOD mice, T cells with a GC Tfh phenotype were found at disease sites. CXCR3(+) CCR6(-) (Tfh1) subset bias was observed among GC Tfh cells infiltrating the pancreas of NOD mice, which was enhanced by loss of SAP NOD T cells override SAP requirement to undergo activation and proliferation in response to Ag presentation, demonstrating the potential for productive cognate T-B lymphocyte interactions in T1D-prone mice. We find that SAP is essential when autoantibody-driven immune complexes promote inflammation but is not required for effective organ-specific autoimmune attack. Thus, Tfh induced in classic GC reactions are dispensable for T1D, but the autoimmune process in the NOD model retains pathogenic Tfh without SAP.