| First Author | Ferris ST | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 13 | Pages | e2219956120 |
| PubMed ID | 36940342 | Mgi Jnum | J:339363 |
| Mgi Id | MGI:7522212 | Doi | 10.1073/pnas.2219956120 |
| Citation | Ferris ST, et al. (2023) WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis. Proc Natl Acad Sci U S A 120(13):e2219956120 |
| abstractText | 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 beta 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 beta 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 beta cell damage. |
