WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis.

The events that initiate autoimmune diabetes in nonobese diabetic (NOD) mice remain poorly understood. CD4 and CD8 T cells are both required to develop disease, but their relative roles in initiating disease are unclear. To test whether CD4 T cell infiltration into islets requires damage to β cells induced by autoreactive CD8 T cells, we inactivated in nonobese diabetic (NOD) mice (NOD.) using CRISPR/Cas9 targeting to eliminate cross-presentation by type 1 conventional dendritic cells (cDC1s). Similar to C57BL/6 mice, cDC1 in NOD. mice are unable to cross-present cell-associated antigens to prime CD8 T cells, while cDC1 from heterozygous NOD. mice cross-present normally. Further, NOD. mice fail to develop diabetes while heterozygous NOD. mice develop diabetes similarly to wild-type NOD mice. NOD. mice remain capable of processing and presenting major histocompatibility complex class II (MHC-II)-restricted autoantigens and can activate β cell-specific CD4 T cells in lymph nodes. However, disease in these mice does not progress beyond peri-islet inflammation. These results indicate that the priming of autoreactive CD8 T cells in NOD mice requires cross-presentation by cDC1. Further, autoreactive CD8 T cells appear to be 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.