与活化单核细胞的相互作用可增强人CD4+CD45ro+CD25+CD127（低表达）调节性T细胞的细胞因子表达和抑制活性。
Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127(low) regulatory T cells.
作者信息
Walter Gina J, Evans Hayley G, Menon Bina, Gullick Nicola J, Kirkham Bruce W, Cope Andrew P, Geissmann Frédéric, Taams Leonie S
机构信息
King's College London, London, UK.
出版信息
Arthritis Rheum. 2013 Mar;65(3):627-38. doi: 10.1002/art.37832.
OBJECTIVE
Despite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127(low) FoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Treg cells are converted into proinflammatory interleukin-17 (IL-17)-producing cells by inflammatory mediators and thereby lose their suppressive function. The aim of this study was to investigate whether activated monocytes, which are potent producers of inflammatory cytokines and are abundantly present in the rheumatic joint, induce proinflammatory cytokine expression in human Treg cells and impair their regulatory function.
METHODS
The presence and phenotype of CD4+CD45RO+CD25+CD127(low) T cells (memory Treg cells) and CD14+ monocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with RA were investigated by flow cytometry. Memory Treg cells obtained from healthy control subjects underwent fluorescence-activated cell sorting and then were cocultured with autologous activated monocytes and stimulated with anti-CD3 monoclonal antibodies. Intracellular cytokine expression, phenotype, and function of cells were determined by flow cytometry, enzyme-linked immunosorbent assay, and proliferation assays.
RESULTS
In patients with RA, the frequencies of CD4+CD45RO+CD25+CD127(low) Treg cells and activated CD14+ monocytes were higher in SF compared with PB. In vitro-activated monocytes induced an increase in the percentage of IL-17-positive, interferon-γ (IFNγ)-positive, and tumor necrosis factor α (TNFα)-positive Treg cells as well as IL-10-positive Treg cells. The observed increase in IL-17-positive and IFNγ-positive Treg cells was driven by monocyte-derived IL-1β, IL-6, and TNFα and was mediated by both CD14+CD16- and CD14+CD16+ monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25+FoxP3+CD39+ Treg cell phenotype and showed an enhanced capacity to suppress T cell proliferation and IL-17 production.
CONCLUSION
Treg cells exposed to a proinflammatory environment show increased cytokine expression as well as enhanced suppressive activity.
目的
尽管类风湿关节炎（RA）患者关节中具有调节表型（CD25 + CD127（低）FoxP3 +）的CD4 + T细胞频率较高，但炎症仍持续存在。一种可能的解释是，人类调节性T细胞（Treg细胞）被炎症介质转化为产生促炎细胞因子白细胞介素17（IL - 17）的细胞，从而失去其抑制功能。本研究的目的是调查作为炎症细胞因子的强效生产者且大量存在于风湿性关节中的活化单核细胞是否会诱导人类Treg细胞中促炎细胞因子的表达并损害其调节功能。
方法
通过流式细胞术研究RA患者外周血（PB）和滑液（SF）中CD4 + CD45RO + CD25 + CD127（低）T细胞（记忆性Treg细胞）和CD14 +单核细胞的存在情况及表型。从健康对照受试者获得的记忆性Treg细胞经过荧光激活细胞分选，然后与自体活化单核细胞共培养，并用抗CD3单克隆抗体刺激。通过流式细胞术、酶联免疫吸附测定和增殖测定来确定细胞的细胞内细胞因子表达、表型和功能。
结果
在RA患者中，与PB相比，SF中CD4 + CD45RO + CD25 + CD127（低）Treg细胞和活化CD14 +单核细胞的频率更高。体外活化的单核细胞诱导IL - 17阳性、干扰素 - γ（IFNγ）阳性和肿瘤坏死因子α（TNFα）阳性Treg细胞以及IL - 10阳性Treg细胞的百分比增加。观察到的IL - 阳性和IFNγ阳性Treg细胞的增加是由单核细胞衍生的IL - 1β、IL - 6和TNFα驱动的，并且由CD14 + CD16 -和CD14 + CD16 +单核细胞亚群介导。尽管细胞因子表达增强，但细胞仍保持其CD25 + FoxP3 + CD39 + Treg细胞表型，并显示出增强的抑制T细胞增殖和IL - 17产生的能力。
结论
暴露于促炎环境的Treg细胞表现出细胞因子表达增加以及抑制活性增强。
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