Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Receptors.
Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Receptors.
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DOI：
10.1038/s41598-018-29262-4
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发表时间：
2018-07-19
影响因子：
4.6
通讯作者：
Denvir J
中科院分区：
文献类型：
--
作者：
McAleer JP;Fan J;Roar B;Primerano DA;Denvir J
Th17细胞有助于黏膜表面的宿主防御，但当针对自身抗原时也会引发自身免疫性疾病。确定调节Th17细胞分化和/或细胞因子产生的治疗靶点具有相当大的价值。在此，我们研究了用诱导Th17的细胞因子处理的人CD4 T细胞中芳烃受体（AhR）依赖的转录组。我们表明，AhR对人CD4 T细胞中IL - 17和IL - 22的产生有相互调节作用。全基因表达分析显示，AhR的连接降低了IL21的表达，这与在用诱导Th17的细胞因子培养过程中RORC的延迟上调相关。一些AhR依赖的基因在细胞组装、组织、发育、生长和增殖中具有已知的作用。我们进一步表明，在AhR激动剂FICZ存在的情况下，GPR15、GPR55和GPR68的表达与IL - 22的产生呈正相关。用劳拉西泮衍生物奥杰林激活GPR68导致T细胞分泌的IL - 22和IL - 10受到抑制，而对IL - 17没有影响。在中性Th0条件下，奥杰林和Gq/11受体抑制剂YM254890减弱了FICZ对IL - 22的诱导。这些数据揭示了人CD4 T细胞中AhR依赖的转录组，并表明AhR调节T细胞功能的机制可能部分依赖于包括GPR68在内的Gq偶联受体。
Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell differentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)-dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no effect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR-dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68.
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影响因子：
4.9
作者：
de Vallière C;Wang Y;Eloranta JJ;Vidal S;Clay I;Spalinger MR;Tcymbarevich I;Terhalle A;Ludwig MG;Suply T;Fried M;Kullak-Ublick GA;Frey-Wagner I;Scharl M;Seuwen K;Wagner CA;Rogler G
通讯作者：
Rogler G
影响因子：
30.5
作者：
Duhen, Thomas;Geiger, Rebekka;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
9.8
作者：
Jordan, Catherine T.;Cao, Li;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
影响因子：
16.6
作者：
Downs-Canner S;Berkey S;Delgoffe GM;Edwards RP;Curiel T;Odunsi K;Bartlett DL;Obermajer N
通讯作者：
Obermajer N
影响因子：
64.5
作者：
Gaublomme JT;Yosef N;Lee Y;Gertner RS;Yang LV;Wu C;Pandolfi PP;Mak T;Satija R;Shalek AK;Kuchroo VK;Park H;Regev A
通讯作者：
Regev A