Deletion of Vβ3 ⁺ CD4 ⁺ T cells by endogenous mouse mammary tumor virus 3 prevents type 1 diabetes induction by autoreactive CD8 ⁺ T cells

Abstract

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 ( Ctla4, Tnfrsf9, Il2/Il21 ), peptide presentation ( H2-A g7 , B2m ), and T cell receptor (TCR) signaling ( Ptpn22 ). Here, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded mammary tumor virus ( Mtv )3 provirus as a genetic element affecting CD4 + /CD8 + T cell interactions through an additional mechanism, altering the TCR repertoire. Mtv3 encodes a superantigen (SAg) that deletes the majority of Vβ3 + thymocytes in NOD mice. Ablating Mtv3 and restoring Vβ3 + T cells has no effect on spontaneous T1D development in NOD mice. However, transferring Mtv3 to C57BL/6 (B6) mice congenic for the NOD H2 g7 MHC haplotype (B6. H2 g7 ) 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 Vβ3 + CD4 + T cells, which unless deleted by Mtv3 , accumulate in insulitic lesions triggering in B6 background mice the pathogenic activation of diabetogenic CD8 + T cells. Our findings provide evidence that endogenous Mtv SAgs can influence autoimmune responses. Furthermore, since most common mouse strains have gaps in their TCR Vβ repertoire due to Mtvs , it raises questions about the role of Mtvs in other mouse models designed to reflect human immune disorders.