Unexpected STAT3-mediated mechanisms of regulation of effector Th17 function in autoimmunity

Abstract

Abstract Th17 cells have been linked to the emergence of many autoimmune inflammatory conditions as well as defense against fungal pathogens. Early differentiation and expansion of Th17 cells relies on key cytokines that signal through STAT3, including IL-6 and IL-21. Later STAT3-dependent signals from IL-23 are critical for gain of inflammatory function by effector Th17 cells. Thus, development of drugs that target STAT3 or its upstream receptors are a major research focus to alleviate disease. However, the requirements for STAT3 signaling in effector Th17 cells remain elusive. Here, we developed a model to study the effect of STAT3 deficiency specifically in effector Th17 cells in EAE, an animal model of multiple sclerosis. Our data show that mice lacking STAT3 in effector Th17 cells are resistant to EAE development. Unexpectedly, we demonstrate that in Th17 cells, STAT3 is not required for maintenance of Th17 lineage commitment or Th17 cytokine production in vivo. To determine mechanisms by which STAT3 regulates Th17 effector cells to promote development of autoimmune inflammation, we performed bioinformatics analysis of the transcriptome of effector Th17 cells isolated from lymph nodes (LN) at day 10 (onset) of EAE. This revealed that STAT3 regulates expression of genes associated with particular cell-death pathways, and pathways associated with proliferation and T cell mediated tissue damage. Corresponding to these changes in gene expression, we found that STAT3 deficient effector Th17 cells were reduced in numbers in LN and target tissue during EAE. Our data reveal a hitherto unappreciated mechanism for STAT3 in regulating effector Th17 cells, which have major implications for use of STAT3-targeted therapies.