Immunology and Allergy, Swiss Centre for Applied Human Toxicology, University Hospital and School of Medicine, Geneva, Switzerland.
Eur J Immunol. 2010 Sep;40(9):2450-9. doi: 10.1002/eji.201040461.
Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-gamma, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4(+) T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4(+) T cells to produce IL-22 without IL-17 and IFN-gamma. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161(+) Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4(+) T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage.
芳基烃受体（AHR）的配体是一种介导二恶英效应的转录因子，有利于 Th17 分化，并在小鼠中加重自身免疫。我们研究了 AHR 配体如何影响人类 T 细胞的极化。我们发现，高亲和力和稳定的 AHR 配体二恶英以及天然的 AHR 配体 6-甲酰基吲哚并[3,2-b]咔唑诱导下游 AHR 靶标细胞色素 P450A1，而不影响 IFN-γ，它们增强了 IL-22，同时减少了 CD4(+)T 细胞产生的 IL-17A。特异性 AHR 抑制剂 CH-223191 消除了这些效应。此外，阻断 IL-23 和 IL-1，它们对 Th17 扩增很重要，可显著降低 IL-17A 但不影响 IL-22 的产生。AHR 激动剂降低了 Th17 主转录因子维甲酸相关孤儿受体 C（RORC）的表达，而不影响 T-bet、GATA-3 和 Foxp3。它们还降低了 IL-23 受体的表达。重要的是，AHR 配体不仅减少了 Th17 细胞的数量，而且还在没有 IL-17 和 IFN-γ 的情况下诱导幼稚 CD4(+)T 细胞产生 IL-22。此外，IL-22 单产者不表达 CD161，这将它们与 CD161(+)Th17 细胞区分开来。因此，我们的数据提供了令人信服的证据，表明 AHR 激活参与塑造人类 CD4(+)T 细胞极化，有利于出现一种独特的 IL-22 产生细胞亚群，它们与 Th17 谱系无关。
