T–B Lymphocyte Interactions Promote Type 1 Diabetes Independently of SLAM-Associated Protein

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.

Factors Governing B Cell Recognition of Autoantigen and Function in Type 1 Diabetes

“…Anti-insulin B cells can spontaneously adopt a germinal center phenotype and undergo limited class switching in NOD.VH125 SD mice in vivo [35], which is dramatically enhanced by the presence of anti-insulin 8F10 T cells following co-transfer into Rag1-deficient NOD recipients [46]. In contrast to these studies indicating T1D dependence on germinal center formation, ~50% of NOD.SAP-deficient mice develop diabetes, despite showing a strong, albeit incomplete, reduction in germinal center B cells [119].…”

“…In contrast to these studies indicating T1D dependence on germinal center formation, ~50% of NOD. SAP -deficient mice develop diabetes, despite showing a strong, albeit incomplete, reduction in germinal center B cells [ 119 ].…”

T follicular helper cells and T follicular regulatory cells in autoimmune diseases

“…Unlike systemic autoimmune disease, Tfh cells are programmed differently in T1D. Although T-B cell interactions are essential to driving high-affinity islet autoantibody production predicting T1D development, the b-cell destruction can arise independently of autoantibody (91,96,147). Both Tfh and Tph cells were increased and associated with T1D progression in human and mouse models by producing IL-21 and recruiting and activating B cells in the pancreas (91)(92)(93)(94)(95).…”

“…Both Tfh and Tph cells were increased and associated with T1D progression in human and mouse models by producing IL-21 and recruiting and activating B cells in the pancreas (91)(92)(93)(94)(95). Furthermore, pathogenic Tfh1 cells were observed in the pancreas and promoted T1D development in nonobese diabetic (NOD) mice (96). Tfr cells were decreased and had attenuated suppressive ability in the peripheral blood, spleen, and pancreatic lymph nodes of T1D patients.…”

B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes

“…SLAM-associated protein (SAP) is necessary for classic germinal center reactions and affinity-matured antibody responses [ 67 , 68 , 69 , 70 ]. Germinal center B cells are reduced in SAP-deficient NOD mice, yet organized tertiary lymphoid structures form in the islets unabated, and T1D still develops in ~50% of mice [ 71 ]. Numerous islet-specific T cell receptors (TCRs) isolated from NOD mice exhibit weak binding to cognate peptides [ 72 , 73 , 74 ].…”