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p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

机译：p53通过诱导促凋亡SAP促进T细胞稳态

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Lack of functional SAP protein, due to gene deletion or mutation, is the cause of X-linked lymphoproliferative disease (XLP), characterized by functionally impaired T and NK cells and a high risk of lymphoma development. We have demonstrated earlier that SAP has a pro-apoptotic function in T and B cells. Deficiency of this function might contribute to the pathogenesis of XLP. We have also shown that SAP is a target of p53 in B cell lines. In the present study, we show that activated primary T cells express p53, which induces SAP expression. p53 is functional as a transcription factor in activated T cells and induces the expression of p21, PUMA and MDM2. PARP cleavage in the late phase of activation indicates that T cells expressing high levels of SAP undergo apoptosis. Modifying p53 levels using Nutlin-3, which specifically dissociates the MDM2-p53 interaction, was sufficient to upregulate SAP expression, indicating that SAP is a target of p53 in T cells. We also demonstrated p53's role as a transcription factor for SAP in activated T cells by ChIP assays. Our result suggests that p53 contributes to T cell homeostasis through the induction of the pro-apoptotic SAP. A high level of SAP is necessary for the activation-induced cell death that is pivotal in termination of the T cell response.
机译：由于基因缺失或突变而导致的功能性SAP蛋白质缺乏是X连锁淋巴增生性疾病（XLP）的病因，其特征是功能性T细胞和NK细胞受损以及淋巴瘤发展的高风险。先前我们已经证明SAP在T和B细胞中具有促凋亡功能。该功能的缺乏可能会导致XLP的发病。我们还表明，SAP是B细胞系p53的靶标。在本研究中，我们显示激活的原代T细胞表达p53，从而诱导SAP表达。 p53在活化的T细胞中起转录因子的作用，并诱导p21，PUMA和MDM2的表达。激活后期的PARP裂解表明，表达高水平SAP的T细胞经历凋亡。使用能特异性解离MDM2-p53相互作用的Nutlin-3修饰p53水平足以上调SAP表达，表明SAP是T细胞中p53的靶标。通过ChIP分析，我们还证明了p53在活化T细胞中作为SAP转录因子的作用。我们的结果表明，p53通过诱导促凋亡SAP促进T细胞稳态。对于激活诱导的细胞死亡而言，高水平的SAP是必需的，这对于终止T​​细胞反应至关重要。

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