T-B lymphocyte interactions mediated by SLAM-associated protein (SAP) are essential for diabetes in transgenic anti-insulin VH125(SD).NOD mice

Abstract Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing beta cells. An essential role for B lymphocytes in the disease process and molecular signatures for T follicular helper cells (Tfhs) in T1D point to the importance of T-B lymphocyte interactions in the pathological process. To understand mechanisms that underpin these T-B interactions, we introduced deficiency of the signaling lymphocyte activation molecular (SLAM)-associated protein (SAP) into VH125SD.NOD mice. In VH125SD.NOD mice a targeted anti-insulin VH gene generates a small population of anti-insulin B lymphocytes that are highly diabetogenic yet are functionally silent for autoantibody production. We find that SAPko dramatically eliminates germinal centers in spleen, pancreatic draining lymph nodes and pancreas. However, insulitis was similar between SAP-sufficient and SAPko VH125SD.NOD mice early in T1D development (8–12 weeks old) but differed later in disease onset (13–17 weeks old). Strikingly, SAP is essential for T1D development, as SAPko VH125SD.NOD mice did not develop T1D. Despite elimination of germinal centers, the numbers of Tfh cells were largely unaffected in the absence of SAP. These findings suggest that prolonged T-B lymphocyte conjugates maintained by SAP are not required for retaining Tfhs; however, these interactions maybe essential for the genesis of pathogenic Tfhs when functionally silent B lymphocytes recognize a beta cell autoantigen.