STAT4 influences the expression of IL-10 in Th17 cells

Abstract

Abstract Autoimmune diseases such as Multiple Sclerosis (MS), Rheumatoid Arthritis (RA) and Crohn’s Disease (CD) affect more than twenty million people in the United States. While the exact etiology of most autoimmune diseases is unknown, single nucleotide polymorphisms in the STAT4 locus are associated with an elevated risk of developing various autoimmune diseases. Specifically, in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), STAT4 is essential for the development of neuroinflammation. Interestingly, STAT4 is a transcription factor known to be important for Th1 cell differentiation, however we and others have demonstrated that many Th1 associated molecules such as IL-12, IFNγ and Tbet are dispensable for EAE. These data lead us to postulate that STAT4 functions in another effector CD4 T cell, Th17 cells, to drive neuroinflammation. Using an adoptive transfer model, we find that STAT4 is required in a Th17-mediated EAE. Transcriptional profiling of the adoptively transferred Th17 cells reveals that STAT4 influences the expression of over 200 genes, one of them being the immunosuppressive cytokine IL-10. Strikingly, we find an indirect relationship between STAT4 and IL-10 in Th17 cells as well as T regulatory 1 (Tr1) cells. We hypothesize that STAT4 regulates the balance between Th17 and Tr1 cells in the context of autoimmune inflammation. Together, these data illustrate a novel role for STAT4 in controlling the functional and plastic properties of Th17 cells, and this may provide a promising therapeutic target for patients affected by Th17 driven autoimmune diseases.