Functional characterization and gene expression analysis of CD4+ CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Functional characterization and gene expression analysis of CD4+ CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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DOI：
10.4049/jimmunol.181.4.2382
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发表时间：
2008-08-15
期刊：
影响因子：
--
通讯作者：
Kerkvliet NI
中科院分区：
文献类型：
--
作者：
Marshall NB;Vorachek WR;Steppan LB;Mourich DV;Kerkvliet NI
尽管2，3，7，8-四氯二苯并对二恶英(TCDD)的作用是通过与芳烃受体(AhR)的结合和激活来实现的，但随后导致免疫抑制的生化和分子变化还不是很清楚。在急性B6转B6D2F1移植物抗宿主反应中暴露于TCDD的小鼠不会发生疾病，最近已被证明与表达CD25并在体外表现出抑制功能的CD4+T细胞的生成有关。这项研究的目的是通过与自然调节性CD4+T细胞(T-regs)和赋形剂处理的细胞进行比较和对比，进一步表征这些CD4+细胞(TCDD-CD4+细胞)。检测细胞无能、抑制功能和细胞因子的产生。我们发现TCDD-CD4+细胞在各种刺激下活跃增殖，但抑制IL-2的产生和效应性T细胞的增殖。与自然T-Regs一样，TCDD-CD4+细胞不产生IL-2，其抑制功能是接触依赖性的，但通过糖皮质激素诱导的TNFR(GITR)被共刺激取消。TCDD-CD4+细胞在多克隆和同种异体抗原刺激下也会分泌大量的IL-10。TCDCD4+细胞中有几个基因显著上调，包括转化生长因子β3、Blimp-1和颗粒酶B，以及与IL12-Rb2信号通路相关的基因。STAT4的磷酸化水平表明，TCDD-CD4+细胞对IL-12的反应性增强。只有2%的TCDD-CD4+细胞表达Foxp3，这表明AhR不依赖于Foxp3的抑制活性。TCDD通过激活AhR产生具有调节功能的CD4+细胞，可能是诱导T-regs的一条新途径。
Although the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated through binding and activation of the aryl hydrocarbon receptor (AhR), the subsequent biochemical and molecular changes that confer immune suppression are not well understood. Mice exposed to TCDD during an acute B6-into-B6D2F1 graft-vs-host response do not develop disease, and recently this has been shown to correlate with the generation of CD4+ T cells that express CD25 and demonstrate in vitro suppressive function. The purpose of this study was to further characterize these CD4+ cells (TCDD-CD4+ cells) by comparing and contrasting them with both natural regulatory CD4+ T cells (T-regs) and vehicle-treated cells. Cellular anergy, suppressive functions, and cytokine production were examined. We found that TCDD-CD4+ cells actively proliferate in response to various stimuli but suppress IL-2 production and the proliferation of effector T cells. Like natural T-regs, TCDD-CD4+ cells do not produce IL-2 and their suppressive function is contact dependent but abrogated by costimulation through glucocorticoid-induced TNFR (GITR). TCDD-CD4+ cells also secrete significant amounts of IL-10 in response to both polyclonal and alloantigen stimuli. Several genes were significantly up-regulated in TCDD-CD4+ cells including TGF-β3, Blimp-1, and granzyme B, as well as genes associated with the IL12-Rb2 signaling pathway. TCDD-CD4+ cells demonstrated an increased responsiveness to IL-12 as indicated by the phosphorylation levels of STAT4. Only 2% of TCDD-CD4+ cells express Foxp3, suggesting that the AhR does not rely on Foxp3 for suppressive activity. The generation of CD4+ cells with regulatory function mediated through activation of the AhR by TCDD may represent a novel pathway for the induction of T-regs.
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介导同种异体移植耐受性的FOXP3+ T调节细胞的募集取决于CCR4趋化因子受体。
影响因子：
15.3
作者：
Lee, I;Wang, LQ;Wells, AD;Dorf, ME;Ozkaynak, E;Hancock, WW
通讯作者：
Hancock, WW
影响因子：
15.3
作者：
Apostolou, I;von Boehmer, H
通讯作者：
von Boehmer, H
影响因子：
4.5
作者：
Camacho, IA;Hassuneh, MR;Nagarkatti, PS
通讯作者：
Nagarkatti, PS
影响因子：
7.8
作者：
Bandyopadhyay, Balaji;Fan, Jianhua;Guan, Shengxi;Li, Yong;Chen, Mei;Woodley, David T;Li, Wei
通讯作者：
Li, Wei
影响因子：
4.4
作者：
Gondek, DC;Lu, LF;Noelle, RJ
通讯作者：
Noelle, RJ