首页> 外文期刊>The Journal of Immunology: Official Journal of the American Association of Immunologists >Ligation of Retinoic Acid Receptor alpha Regulates Negative Selection of Thymocytes by Inhibiting Both DNA Binding of nur77 and Synthesis of Bim.
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Ligation of Retinoic Acid Receptor alpha Regulates Negative Selection of Thymocytes by Inhibiting Both DNA Binding of nur77 and Synthesis of Bim.

机译:维甲酸受体α的连接通过抑制nur77的DNA结合和Bim的合成来调节胸腺细胞的阴性选择。

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Negative selection refers to the selective deletion of autoreactive thymocytes. Its molecular mechanisms have not been well defined. Previous studies in our laboratory have demonstrated that retinoic acids, physiological ligands for the nuclear retinoid receptors, selectively inhibit TCR-mediated death under in vitro conditions, and the inhibition is mediated via the retinoic acid receptor (RAR) alpha. The present studies were undertaken to investigate whether ligation of RARalpha leads to inhibition of TCR-mediated death in vivo and to identify the molecular mechanisms involved. Three models of TCR-mediated death were studied: anti-CD3-mediated death of thymocytes in wild-type mice, and Ag- and bacterial superantigen-driven thymocyte death in TCR-transgenic mice expressing a receptor specific for a fragment of pigeon cytochrome c in the context of the E(k) (class II MHC) molecule. Our data demonstrate that the molecular program of both anti-CD3- and Ag-driven, but not that of superantigen-mediated apoptosis involves up-regulation of nur77, an orphan nuclear receptor, and bim, a BH3-only member of the proapoptotic bcl-2 protein family, proteins previously implicated to participate in the negative selection. Ligation of RARalpha by the synthetic agonist CD336 inhibited apoptosis, DNA binding of nur77, and synthesis of bim induced by anti-CD3 or the specific Ag, but had no effect on the superantigen-driven cell death. Our data imply that retinoids are able to inhibit negative selection in vivo as well, and they interfere with multiple steps of the T cell selection signal pathway.
机译:负选择是指自身反应性胸腺细胞的选择性缺失。其分子机制还没有很好的定义。我们实验室中的先前研究表明,视黄酸是核类视黄醇受体的生理配体,在体外条件下选择性抑制TCR介导的死亡,并且该抑制作用是通过视黄酸受体(RAR)α介导的。进行本研究以调查RARα的连接是否导致体内抑制TCR介导的死亡并鉴定涉及的分子机制。研究了三种TCR介导的死亡模型:野生型小鼠中抗CD3介导的胸腺细胞死亡,以及表达对鸽子细胞色素c片段具有特异性的受体的TCR转基因小鼠中由Ag和细菌超抗原驱动的胸腺细胞死亡。在E(k)(II类MHC)分子中。我们的数据表明,抗CD3和Ag驱动的分子程序,而不是超抗原介导的凋亡的分子程序,都涉及上调nur77(一个孤儿核受体)和bim(前凋亡bcl的仅BH3成员) -2蛋白家族,以前牵涉参与负选择的蛋白。合成激动剂CD336连接RARalpha可以抑制细胞凋亡,nur77的DNA结合以及抗CD3或特异性Ag诱导的bim合成,但对超抗原驱动的细胞死亡没有影响。我们的数据表明,类维生素A也能够抑制体内的负选择,并且它们干扰T细胞选择信号通路的多个步骤。

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