The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4⁺ T cells, CD19⁺ B cell, and CD14⁺ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4⁺ T cell differentiation, proliferation and apoptosis. We further examined TGFβ-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4⁺ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4⁺ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4⁺ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4⁺ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4⁺ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4⁺ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4⁺ T cells. Defective EZH2 in CD4⁺ T cells might contribute to Treg deficiency in RA.

Zeste同系物2（EZH2）的染色质修饰剂增强剂使组蛋白H3（H3K27）的赖氨酸27甲基化，并调节T细胞分化。但是，EZH2在类风湿性关节炎（RA）发病机理中的潜在作用仍然难以捉摸。我们分析了从未接受过主动治疗的RA患者和健康对照（HC）的PBMC，CD4 ⁺ T细胞，CD19 ⁺ B细胞和CD14 ⁺单核细胞中EZH2的表达。我们还使用EZH2抑制剂GSK126抑制了EZH2表达，并测量了CD4 ⁺ T细胞的分化，增殖和凋亡。我们进一步检查了EZH2抑制的CD4 ^+中的TGFβ-SMAD和RUNX1信号通路T细胞。最后，我们通过中和关键的促炎细胞因子探讨了RA滑液和成纤维样滑膜细胞（FLS）对EZH2的调节机制。RA患者的PBMC和CD4 ⁺ T细胞中EZH2表达低于HC患者。EZH2抑制抑制CD4 ⁺ T细胞中的调节性T细胞（Tregs）分化和FOXP3转录，并下调RUNX1和上调SMAD7表达。RA滑液和成纤维细胞样滑膜细胞抑制了CD4 ⁺ T细胞中EZH2的表达，该表达被抗-IL17抗体部分中和。总之，CD4 ^+中的EZH2RA患者的T细胞减毒，通过下调CD4 ⁺ T细胞中的RUNX1和上调SMAD7抑制FOXP3转录，最终抑制Tregs的分化。RA滑液中的IL17可能促进CD4 ⁺ T细胞中EZH2的下调。CD4 ⁺ T细胞中EZH2缺陷可能是RA中Treg缺乏的原因。