Veldhoen Marc, Hirota Keiji, Westendorf Astrid M, Buer Jan, Dumoutier Laure, Renauld Jean-Christophe, Stockinger Brigitta
Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK.
Nature. 2008 May 1;453(7191):106-9. doi: 10.1038/nature06881. Epub 2008 Mar 23.
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor best known for mediating the toxicity of dioxin. Environmental factors are believed to contribute to the increased prevalence of autoimmune diseases, many of which are due to the activity of T(H)17 T cells, a new helper T-cell subset characterized by the production of the cytokine IL-17. Here we show that in the CD4+ T-cell lineage of mice AHR expression is restricted to the T(H)17 cell subset and its ligation results in the production of the T(H)17 cytokine interleukin (IL)-22. AHR is also expressed in human T(H)17 cells. Activation of AHR by a high-affinity ligand during T(H)17 cell development markedly increases the proportion of T(H)17 T cells and their production of cytokines. CD4+ T cells from AHR-deficient mice can develop T(H)17 cell responses, but when confronted with AHR ligand fail to produce IL-22 and do not show enhanced T(H)17 cell development. AHR activation during induction of experimental autoimmune encephalomyelitis causes accelerated onset and increased pathology in wild-type mice, but not AHR-deficient mice. AHR ligands may therefore represent co-factors in the development of autoimmune diseases.
芳烃受体(AHR)是一种依赖配体的转录因子,因介导二噁英的毒性而广为人知。环境因素被认为与自身免疫性疾病患病率的增加有关,其中许多疾病是由辅助性T细胞17(TH17)的活性引起的,TH17是一种新的辅助性T细胞亚群,其特征是产生细胞因子白细胞介素-17(IL-17)。在这里,我们表明,在小鼠的CD4+T细胞谱系中,AHR的表达仅限于TH17细胞亚群,其连接会导致TH17细胞因子白细胞介素(IL)-22的产生。AHR也在人类TH17细胞中表达。在TH17细胞发育过程中,高亲和力配体激活AHR会显著增加TH17 T细胞的比例及其细胞因子的产生。来自AHR缺陷小鼠的CD4+T细胞可以产生TH17细胞反应,但在接触AHR配体时不能产生IL-22,也不会表现出增强的TH17细胞发育。在实验性自身免疫性脑脊髓炎诱导过程中激活AHR会导致野生型小鼠发病加速和病理变化增加,但AHR缺陷小鼠则不会。因此,AHR配体可能是自身免疫性疾病发展中的辅助因子。