WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis.

Abstract

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