STAT3 regulation of effector Th17 cells and its implications for treatment of autoimmunity

Abstract

Abstract Th17 cells are implicated in the pathogenesis of many autoimmune and inflammatory diseases, including multiple sclerosis (MS) and rheumatoid arthritis. Early Th17 cell development relies on key cytokines that signal through STAT3, including IL-6, IL-21 and IL-23. These signals are critical for gain of effector Th17 cell functions, including the expression of the inflammatory cytokines IL-17, IFN-γ and GM-CSF. Thus, development of drugs that target STAT3 signaling are a major research focus to alleviate disease. However, the functions of STAT3 signaling post Th17 cell development in late effector cells remain elusive. Here, we developed a model to study STAT3 deficiency effects specifically in late effector Th17 cells, termed Th17ΔSTAT3. We show that Th17ΔSTAT3 mice are resistant to development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To determine mechanisms by which STAT3 regulates Th17 cell pathogenicity we performed bioinformatics analysis of effector Th17 cell transcriptome. Corresponding to changes in gene expression, we found that Th17ΔSTAT3 cells were reduced in numbers in lymph nodes and CNS during EAE. We demonstrated that STAT3 is critical to drive G1 to S phase transition of the cell cycle by regulating key cell cycle genes. Moreover, we found that STAT3 maintains Th17 cell mitochondrial integrity. Unexpectedly, our data show that lineage specific gene expression, including cytokines, is not altered in Th17ΔSTAT3 cells. However, Th17ΔSTAT3 cells have reduced IL-17 expression, but not IFN-γ or GM-CSF upon antigen restimulation. Our data reveal hitherto unknown mechanisms for STAT3 in regulating effector Th17 cells, which have major implications for use of Th17 cell-targeted therapies.