OBJECTIVE To study the involvement of Treg cells expressing tumor necrosis factor receptor type II (TNFRII) in exerting control of inflammation in experimental models and in the response to anti-TNF treatments in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA). METHODS The role of TNFRII in Treg cells was explored using a multilevel translational approach. Treg cell stability was evaluated by analyzing the methylation status of the Foxp3 locus using bisulfite sequencing. Two models of inflammation (imiquimod-induced skin inflammation and delayed-type hypersensitivity arthritis [DTHA]) were induced in TNFRII-/- mice, with or without transfer of purified CD4+CD25+ cells from wild-type (WT) mice. In patients with RA and those with SpA, the evolution of the TNFRII+ Treg cell population before and after targeted treatment was monitored. RESULTS Foxp3 gene methylation in Treg cells was greater in TNFRII-/- mice than in WT mice (50% versus 36.7%). In cultured Treg cells, TNF enhanced the expression, maintenance, and proliferation of Foxp3 through TNFRII signaling. Imiquimod-induced skin inflammation and DTHA were aggravated in TNFRII-/- mice (P < 0.05 for mice with skin inflammation and P < 0.0001 for mice with ankle swelling during DTHA compared to WT mice). Adoptive transfer of WT mouse Treg cells into TNFRII-/- mice prevented aggravation of arthritis. In patients with RA receiving anti-TNF treatments, but not those receiving tocilizumab, the frequency of TNFRII+ Treg cells was increased at 3 months of treatment compared to baseline (mean ± SEM 65.2 ± 3.1% versus 49.1 ± 5.5%; P < 0.01). In contrast, in anti-TNF-treated patients with SpA, the frequency of TNFRII+ Treg cells was not modified. CONCLUSION TNFRII expression identifies a subset of Treg cells that are characterized by stable expression of Foxp3 via gene hypomethylation, and adoptive transfer of TNFRII-expressing Treg cells ameliorates inflammation in experimental models. Expansion and activation of TNFRII+ Treg cells may be one of the mechanisms by which anti-TNF agents control inflammation in RA, but not in SpA.

中文翻译：

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类肿瘤坏死因子受体II在FoxP3稳定性中的参与，并作为类风湿性关节炎中抗肿瘤坏死因子治疗特异扩增的Treg细胞的标志物。

目的研究类风湿关节炎（RA）或脊柱关节炎（SpA）患者中表达Treg细胞表达肿瘤坏死因子受体II型（TNFRII）在炎症控制和抗TNF治疗反应中的作用。方法采用多级翻译方法探讨TNFRII在Treg细胞中的作用。通过使用亚硫酸氢盐测序分析Foxp3基因座的甲基化状态来评估Treg细胞的稳定性。在TNFRII-/-小鼠中诱导了两种炎症模型（咪喹莫特诱发的皮肤炎症和迟发型超敏性关节炎[DTHA]），无论是否转移了野生型（WT）小鼠的纯化CD4 + CD25 +细胞。在患有RA和SpA的患者中，监测靶向治疗前后TNFRII + Treg细胞群体的演变。结果TNFRII-/-小鼠的Treg细胞中Foxp3基因甲基化程度高于野生型小鼠（50％比36.7％）。在培养的Treg细胞中，TNF通过TNFRII信号传导增强Foxp3的表达，维持和增殖。在TNFRII-/-小鼠中，咪喹莫特诱导的皮肤炎症和DTHA加剧（与WT小鼠相比，DTHA皮肤炎症小鼠的P <0.05，踝关节肿胀的小鼠的P <0.0001）。WT小鼠Treg细胞过继转移到TNFRII-/-小鼠中可预防关节炎的加剧。在接受抗TNF治疗但未接受tocilizumab治疗的RA患者中，与基线相比，治疗3个月时TNFRII + Treg细胞的频率增加（平均值±SEM 65.2±3.1％对49.1±5。5％；P <0.01）。相反，在抗TNF治疗的SpA患者中，TNFRII + Treg细胞的频率未改变。结论TNFRII的表达可识别Treg细胞的一个子集，该子集的特征在于可通过基因低甲基化稳定表达Foxp3，而过表达TNFRII的Treg细胞的过继转移可减轻实验模型中的炎症。TNFRII + Treg细胞的扩增和激活可能是抗TNF药物控制RA（而非SpA）炎症的机制之一。表达TNFRII的Treg细胞的过继转移可改善实验模型中的炎症。TNFRII + Treg细胞的扩增和激活可能是抗TNF药物控制RA（而非SpA）炎症的机制之一。表达TNFRII的Treg细胞的过继转移可改善实验模型中的炎症。TNFRII + Treg细胞的扩增和激活可能是抗TNF药物控制RA（而非SpA）炎症的机制之一。