Yokosawa M, Kondo Y, Tahara M, Iizuka-Koga M, Segawa S, Kaneko S, Tsuboi H, Yoh K, Takahashi S, Matsumoto I, Sumida T
Division of Rheumatology, Department of Internal Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
Division of Nephrology, Department of Medicine, University of Tsukuba, Tsukuba city, Ibaraki, Japan.
Clin Exp Immunol. 2017 Apr;188(1):22-35. doi: 10.1111/cei.12912. Epub 2017 Jan 31.
Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen-induced arthritis was suppressed in T-bet transgenic (T-bet Tg) mice, and T-bet seemed to suppress Th17 differentiation through an interferon (IFN)-γ-independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T-bet over-expression, and we found the new relationship between T-bet and aryl hydrocarbon receptor (AHR). Both T-bet Tg mice and IFN-γ -over-expressing T-bet (T-bet Tg/IFN-γ ) mice showed inhibition of retinoic acid-related orphan receptor (ROR)γt expression and IL-17 production by CD4 T cells cultured under conditions that promote Th-17 differentiation, and decreased IL-6 receptor (IL-6R) expression and signal transducer and activator of transcription-3 (STAT-3) phosphorylation in CD4 T cells. The mRNA expression of ahr and rorc were suppressed in CD4 T cells cultured under Th-17 conditions from T-bet Tg mice and T-bet Tg/IFN-γ mice. CD4 T cells of wild-type (WT) and IFN-γ mice transduced with T-bet-expressing retrovirus also showed inhibition of IL-17 production, whereas T-bet transduction had no effect on IL-6R expression and STAT-3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4 T cells with T-bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)-17 production from CD4 T cells by the addition of AHR ligand with Th17 conditions was cancelled by T-bet over-expression. Our findings suggest that T-bet over-expression-induced suppression of Th17 differentiation is mediated through IFN-γ-independent AHR suppression.
已知多种转录因子可增强或抑制17型辅助性T细胞（Th17）分化。我们之前已经证明，在T-bet转基因（T-bet Tg）小鼠中，胶原诱导的关节炎的发展受到抑制，并且T-bet似乎通过独立于干扰素（IFN）-γ的途径抑制Th17分化，尽管确切机制仍有待阐明。本研究旨在进一步探讨T-bet过表达调控Th17分化的机制，我们发现了T-bet与芳烃受体（AHR）之间的新关系。在促进Th17分化的条件下培养的CD4 T细胞中，T-bet Tg小鼠和过表达IFN-γ的T-bet（T-bet Tg/IFN-γ）小鼠均显示维甲酸相关孤儿受体（ROR）γt表达和IL-17产生受到抑制，并且CD4 T细胞中IL-6受体（IL-6R）表达以及信号转导和转录激活因子3（STAT-3）磷酸化水平降低。在来自T-bet Tg小鼠和T-bet Tg/IFN-γ小鼠的Th17条件下培养的CD4 T细胞中，ahr和rorc的mRNA表达受到抑制。用表达T-bet的逆转录病毒转导的野生型（WT）和IFN-γ小鼠的CD4 T细胞也显示出IL-17产生受到抑制，而T-bet转导对IL-6R表达和STAT-3磷酸化没有影响。有趣的是，在Th17条件下培养的经T-bet转导的CD4 T细胞中，ahr和rorc的mRNA表达受到抑制。在Th17条件下添加AHR配体可增强CD4 T细胞产生白细胞介素（IL）-17，但T-bet过表达可消除这种增强作用。我们的研究结果表明，T-bet过表达诱导的Th17分化抑制是通过独立于IFN-γ的AHR抑制介导的。
