RORC2 Is Involved in T Cell Polarization through Interaction with the FOXP3 Promoter
RORC2 Is Involved in T Cell Polarization through Interaction with the FOXP3 Promoter
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DOI：
10.4049/jimmunol.0903243
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发表时间：
2010-06-01
影响因子：
4.4
通讯作者：
Schmidt-Weber, Carsten B.
中科院分区：
文献类型：
--
作者：
Burgler, Simone;Mantel, Pierre-Yves;Schmidt-Weber, Carsten B.
Th 细胞分化为极化效应 T 细胞的过程可调节针对入侵病原体的特异性免疫，同时允许对共生微生物、无害过敏原或自体 Ag 产生耐受。因此，识别这种极化过程背后的机制对于理解免疫系统如何赋予免疫力和耐受性至关重要。本研究表明视黄酸受体相关孤儿受体 C2 (RORC2) 是 Th17 细胞发育的关键转录因子，可抑制人类 T 细胞中 FOXP3 的表达。尽管 RORC2 在初始 T 细胞中的过度表达会降低 FOXP3 的水平，但小干扰 RNA 介导的 RORC2 敲低会增强其表达。 RORC2 至少部分通过与 FOXP3 启动子上四个 ROR 响应元件中的两个结合来介导这种抑制。 RORC2的敲除可促进FOXP3的高水平，并降低促炎细胞因子β形式的pro-IL-1、IL-6、IL-17A、IFN-γ和TNF-α在分化幼稚T细胞中的表达，这表明RORC2在Th17细胞发育中的作用不仅涉及诱导Th17特征基因，还涉及抑制调节性T细胞特异性 程序。总之，这项研究将 RORC2 确定为转录交叉调节中的极化因子，并为控制免疫耐受与效应免疫反应提供了新的观点。免疫学杂志，2010，184：6161-6169。
The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high FOXP3 levels and decreased expression of proinflammatory cytokines beta form of pro-IL-1, IL-6, IL-17A, IFN-gamma, and TNF-alpha in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17-characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses. The Journal of Immunology, 2010, 184: 6161-6169.