Understanding the role of STAT4 in experimental autoimmune encephalomyelitis

Abstract

Abstract Multiple Sclerosis (MS) is an autoimmune disease that affects over two million people worldwide. MS is characterized by the demyelination of axons in the central nervous system (CNS), leading to vision problems, muscle weakness and poor coordination. Among the various immune cells that contribute to the disease, a subset of CD4 T cells, Th17 cells has been associated with MS pathogenesis. Importantly, IL-23 signaling in Th17 cells is essential for the pathogenicity of these cells. A transcription factor downstream of IL-23 signaling, STAT4, is dispensable for in vivo and in vitro Th17 development, however STAT4 is crucial for the development of CNS inflammation and polymorphisms in STAT4 are linked to MS susceptibility. As STAT4 deficiency does not prevent Th17 differentiation, but still limits inflammation, we hypothesize that STAT4 is necessary for the pathogenic properties of Th17 cells in MS. Using the adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), we find that STAT4 expression by Th17 cells is necessary to induce CNS inflammation. Furthermore, global gene expression analysis indicates that STAT4 regulates the recently described pathogenic and nonpathogenic Th17 gene signatures. In the absence of STAT4, the levels of pathogenic Th17 genes including Tbx21, Il22 and Cxcl3 are significantly reduced, while the expression of nonpathogenic genes including Il10 and Ahr is increased. Interestingly, we find that STAT4 influences Th17 gene expression regardless of the differentiation conditions. Together, these data reveal a novel role of STAT4 in controlling Th17 pathogenicity, which may provide a promising therapeutic target for MS patients.