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

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.

Functional and phenotypic heterogeneity of Th17 cells in health and disease

“…In this context, it may be relevant that reduced levels of the transcription factor, regulatory factor X1 (RFX1), was recently shown to result in reduced histone and DNA methylation. This leads to an increase in Th17 cell differentiation in patients and experimental lupus mice …”

“…This leads to an increase in Th17 cell differentiation in patients and experimental lupus mice. 77 Effector Th17 cells found in the blood and tissues of patients with SLE are implicated in the pathogenesis of the disease. 36 Imbalance in the intestinal microbiome, characterized by reduced Firmicutes:Bacteroidetes ratios, has been reported in SLE and shown to promote Th17 cell differentiation ( Table 2).…”

E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases

“…For the present study, 60 patients with SLE who met the requirements of the Revised Criteria of the American College of Rheumatology (58) for SLE and age-matched healthy females were recruited from outpatient dermatology clinics and inpatient wards. Exclusion criteria were previously described (59). Activity categories were defined on the basis of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores: no activity (SLEDAI = 0-4), mild activity (SLEDAI = 5 to 10), moderate activity (SLEDAI = 11 to 14), and high activity (SLEDAI ≥ 15).…”

“…injection of 500 µL saline (as a control) or pristane (MilliporeSigma). For the ex vivo analysis, experimental mice were sacrificed 8 months after the pristane injection as previously described (59).…”

“…Flow cytometry. Single-cell suspensions were fluorescently labeled as previously described (59). In the case of FoxP3, BCL6, and E4BP4 staining, a FoxP3 staining kit (BD Biosciences) was used for intracellular staining.…”