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