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 Wdfy4 in nonobese diabetic (NOD) mice (NOD.Wdfy4(−/−-)) using CRISPR/Cas9 targeting to eliminate cross-presentation by type 1 conventional dendritic cells (cDC1s). Similar to C57BL/6 Wdfy4(−/−) mice, cDC1 in NOD.Wdfy4(−/−) mice are unable to cross-present cell-associated antigens to prime CD8(+) T cells, while cDC1 from heterozygous NOD.Wdfy4(+/−) mice cross-present normally. Further, NOD.Wdfy4(−/−) mice fail to develop diabetes while heterozygous NOD.Wdfy4(+/−) mice develop diabetes similarly to wild-type NOD mice. NOD.Wdfy4(−/−) 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.