Abstract
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.
Highlights
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
To gain a better understanding of the role that RFX1 plays in Th17 cell differentiation, we measured the mRNA and protein expression levels of RFX1 and IL-17A in CD4+ T cells from a new cohort of Systemic lupus erythematosus (SLE) patients, including 23 active patients and 8 inactive patients, and 14 healthy controls
The mRNA and protein expression levels of RFX1 were significantly decreased in CD4+ T cells of inactive and active SLE patients compared with healthy controls (Fig. 1a–c)
Summary
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. 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. Our previous studies showed that RFX1 regulates the immune-related genes CD11a and CD70 by affecting the epigenetic modifications of the two genes’ loci in CD4+ T cells and that downregulation of RFX1 in CD4+ T cells contributes to the autoimmune response of SLE patients[16,21]. RFX1 functions downstream of signal transducer and activator of transcription factor 3 (STAT3) and IL-6-induced STAT3 activation can reduce the expression of RFX1 These data support a role for RFX1 deficiency in the pathogenesis of SLE, by mediating aberrant Th17 differentiation induced by IL-6 in the inflammatory environment
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