IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation

Nat Commun. 2018 Feb 8;9(1):583. doi: 10.1038/s41467-018-02890-0.


Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells. In vitro, Rfx1 deficiency increases the differentiation of naive CD4+ T cells into Th17 cells, but this effect can be reversed by forced expression of Rfx1. Importantly, RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression, highlighting a non-canonical pathway that regulates differentiation of Th17 cells. Collectively, our findings identify a unique role for RFX1 in Th17-related autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Epigenesis, Genetic*
  • Female
  • HEK293 Cells
  • Humans
  • Interleukin-6 / pharmacology*
  • Jurkat Cells
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Phosphorylation
  • Regulatory Factor X1 / genetics
  • Regulatory Factor X1 / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / genetics
  • Th17 Cells / drug effects*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Young Adult


  • Interleukin-6
  • Regulatory Factor X1
  • STAT3 Transcription Factor