An IL-23/STAT4 axis regulates classical dendritic cell expansion and function in CNS autoimmunity

Abstract Signal transducer and activator of transcription 4 (STAT4) is a critical regulator inflammation in autoimmunity by acting as messenger for pro-inflammatory cytokines including IL-12 IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model multiple sclerosis, germ-line deletion STAT4 mice results resistance to the development paralysis. Here, we examined cell-specific requirements EAE. Using conditional Stat4mutant mice, found that lacking Stat4in CD4 +T cells CD11c +cells are resistant EAE, while Lyz2 susceptible EAE demonstrating cell type requirement expressed activated +classical dendritic (cDCs) CNS at peak Stat4fl/flCD11cCre(Stat4ΔCD11c) exhibit significant decrease cDC expansion CNS, this correlates with diminished numbers T decreased inflammatory cytokine production. Adoptive transfer wild-type DCs into Stat4ΔCD11crescues contrast, transferring Il23r−/−DCs Stat4ΔCD11cdid not rescue development. Transferred were retained lymph nodes suggesting IL-23-STAT4 signaling cDCs promotes their during neuroinflammation. CITE-seq analysis from control Stat4ΔCD11cmice identified STAT4-dependent genes Collectively, our demonstrate required cells, clinical symptoms Thus, study reveals previously unrecognized functions could identify novel therapeutic approaches autoimmunity.