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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4~+CD8~+ thymocytes
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Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4~+CD8~+ thymocytes

机译：CD4〜+ CD8〜+胸腺细胞阴性选择过程中需要共刺激信号来诱导转录因子Nur77

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摘要

A major question in end-stage T cell devel- opment is how T cell receptor(TCR) ligation on immature CD4~+CD8~+ double positive thymocytes is translated into either survival (positive selection) or apoptotic (negative selection) signals. Because different types of antigen- presenting cells (APCs) induce positive or negative selection in the thymus and express different costimulatory molecules, involvement of such costimulatory molecules in determining cell fate of DP thymocytes is considered here. If TCR- generated signals are modulated by APCs, this should be reflected in the activation of distinct biochemical pathways. We here demonstrate that costimulatory signals involved in negative selection also are required for induction of protein expression of Nur77 and its family members. These transcrip- tion factors are critically involved in negative but not positive selection. In contrast, the signals that costimulate negative selection are not required for induction of several molecular events associated with positive selection. These include acti- vation of the immediate early gene Egr-1, the mitogen- activated protein kinase ERK2, and surface expression of the CD69 marker. Thus, costimulation for negative selection selectively provides signals for activation of apoptotic medi- ators. These data provide molecular insights into how TCR- engagement by ligands on different thymic APCs can deter- mine cell fate.
机译：末期T细胞发展中的一个主要问题是如何将未成熟CD4〜+ CD8〜+双阳性胸腺细胞上的T细胞受体（TCR）连接转化为存活（阳性选择）或凋亡（阴性选择）信号。由于不同类型的抗原呈递细胞（APC）在胸腺中诱导阳性或阴性选择并表达不同的共刺激分子，因此在此考虑了这些共刺激分子参与确定DP胸腺细胞的细胞命运。如果TCR产生的信号被APC调节，则这应反映在不同生化途径的激活中。我们在这里证明参与负选择的共刺激信号也是诱导Nur77及其家族成员蛋白表达所必需的。这些转录因子与否定选择有关，而与正选择无关。相反，诱导与正选择相关的若干分子事件并不需要共刺激负选择的信号。这些包括立即早期基因Egr-1的激活，丝裂原活化的蛋白激酶ERK2的激活以及CD69标记的表面表达。因此，针对负选择的共刺激选择性地提供了凋亡调节因子的激活信号。这些数据提供了分子认识，了解配体在不同胸腺APC上的TCR结合如何决定细胞命运。

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