WDFY4 deficiency in NOD mice abrogates autoimmune diabetes and insulitis

Abstract The events that initiate autoimmune diabetes in NOD mice remain poorly understood. CD4 and CD8 T cells are both required but whether either cell initiates disease is unclear. To test whether CD4 T cell infiltration into islet required damage to β cells induced by autoreactive CD8 T cells, we selectively inactivated Wdfy4 in NOD mice (NOD. Wdfy4 -/- ) using CRISPR/Cas9 targeting. Similar to C57BL/6 Wdfy4 -/- mice NOD. Wdfy4 -/- mice develop type 1 conventional dendritic cells (cDC1) that are unable to cross-present cell-associated antigens required to activate CD8 T cells. By contrast, cDC1 from heterozygous Wdfy4 +/- mice can cross-present normally. Heterozygous NOD. Wdfy4 +/- mice develop diabetes similar to NOD mice, but NOD. Wdfy4 -/- mice neither develop diabetes nor prime autoreactive CD8 T cells in vivo . By contrast, NOD. Wdfy4 -/- mice can process and present MHC-II-restricted autoantigens and can activate β cell specific CD4 T cells in lymph nodes, and yet do not develop CD4 T cell infiltration in islets. These results indicate that the priming of autoreactive CD8 T cells in NOD mice requires cross-presentation by cDC1. Further, autoreactive CD8 T cells are required not only to develop diabetes, but to recruit autoreactive CD4 T cells into islets of NOD mice, perhaps in response to progressive β cell damage.