Deletion of Vβ3CD4 T cells by endogenous mouse mammary tumor virus 3 prevents type 1 diabetes induction by autoreactive CD8 T cells.

In both humans and NOD mice, type 1 diabetes (T1D) develops from the autoimmune destruction of pancreatic beta cells by T cells. Interactions between both helper CD4 and cytotoxic CD8 T cells are essential for T1D development in NOD mice. Previous work has indicated that pathogenic T cells arise from deleterious interactions between relatively common genes which regulate aspects of T cell activation/effector function ( ), peptide presentation (, ), and T cell receptor (TCR) signaling (). Here, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded mammary tumor virus ()3 provirus as a genetic element affecting CD4/CD8 T cell interactions through an additional mechanism, altering the TCR repertoire. encodes a superantigen (SAg) that deletes the majority of Vβ3 thymocytes in NOD mice. Ablating and restoring Vβ3 T cells has no effect on spontaneous T1D development in NOD mice. However, transferring to C57BL/6 (B6) mice congenic for the NOD MHC haplotype (B6.) completely blocks their normal susceptibility to T1D mediated by transferred CD8 T cells transgenically expressing AI4 or NY8.3 TCRs. The entire genetic effect is manifested by Vβ3CD4 T cells, which unless deleted by , accumulate in insulitic lesions triggering in B6 background mice the pathogenic activation of diabetogenic CD8 T cells. Our findings provide evidence that endogenous SAgs can influence autoimmune responses. Furthermore, since most common mouse strains have gaps in their TCR Vβ repertoire due to , it raises questions about the role of in other mouse models designed to reflect human immune disorders.