STAT4 in Conventional Dendritic Cells Regulates Pathogenic T Cell Differentiation and Inflammation in Experimental Autoimmune Encephalomyelitis

Abstract Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system (CNS). Signal transducer and activator of transcription 4 (STAT4) is a major regulator of inflammatory in protective immunity and autoimmunity. STAT4 is activated downstream of two cytokines known to mediate the pathogenic T cell differentiation in autoimmune diseases, IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, germ-line deletion of STAT4 in mice results in resistance to the development of EAE. In this study, we investigated the contribution of innate myeloid cells to the phenotype observed in STAT4−/− mice in EAE. Using conditional mutant mice, we immunized mice deficient in STAT4 in myeloid cells and found that mice deficient in STAT4 in CD11c+ cells, but not Lyz2 + cells, are resistant to disease. STAT4fl/flCD11cCre mice are resistant to EAE induction and have inefficient differentiation of the pathogenic IL-17A, GM-CSF, and IFN-γ secreting CD4+ T cells. More importantly, STAT4fl/flCD11cCre mice have a significant decrease of migrated MHCIIhigh+ CD11chigh+CD26+ conventional dendritic cells (cDCs) to the CNS, suggesting a critical role of STAT4 on cDC migration to the CNS. Overall, our results identify a functional requirement of STAT4 in cDCs during EAE induction and propose a potential therapeutic target for autoimmune neuroinflammation diseases.