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 {beta} 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 {beta} 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 {beta} cell damage.