A p53 axis regulates B cell receptor-triggered, innate immune system-driven B cell clonal expansion.
A p53 axis regulates B cell receptor-triggered, innate immune system-driven B cell clonal expansion.
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DOI：
10.4049/jimmunol.1103037
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Mongini PK
中科院分区：
文献类型：
--
作者：
Lee H;Haque S;Nieto J;Trott J;Inman JK;McCormick S;Chiorazzi N;Mongini PK
静止的成熟人B细胞在体外对替代c3d包被抗原和先天免疫系统细胞因子、IL-4和BAFF的反应中经历了克隆扩增然后克隆收缩的动态过程。在这里，我们通过观察cfse标记培养物中受时间和分裂影响的几种促凋亡和抗凋亡蛋白的表达，探索克隆收缩的机制。一些涉及人类和小鼠B细胞的研究结果表明，涉及p53的线粒体依赖性凋亡途径有助于复制母细胞的高AICD易感性。活化的B细胞克隆表现出p53蛋白升高和已知受p53转录直接控制的促凋亡分子Bax、Bad、Puma、Bid和前caspase 6 mRNA/蛋白升高，同时抗凋亡Bcl-2降低。在这些条件下，Bim水平没有增加。研究发现，在aicd易感的复制母细胞中，全长Bid蛋白显著下降，而Bid mRNA则没有，这表明Bid被主动地裂解为短寿命的促凋亡的tBid。通过p53 siRNA转染、p53基因缺失或Bcl-2过表达，AICD减少，尽管没有消除。DNA损伤可能是p53依赖性AICD的触发因素，因为易感淋巴细胞表达的phospho-ATMser1980和phospho-H2AXser139水平均显著升高。激活诱导的胞嘧啶脱氨酶（AID）缺乏会减少但不会减少小鼠B细胞的AICD，这表明AID诱导的DNA损伤只是部分原因。在这种TI克隆扩增途径中p53影响AICD的证据表明，携带p53突变的后代可能在IL-4和BAFF水平升高的周围炎症组织中进行正选择。
Resting mature human B cells undergo a dynamic process of clonal expansion, followed by clonal contraction, during an in vitro response to surrogate C3d-coated antigen and innate immune system cytokines, IL-4 and BAFF. We here explore the mechanism for clonal contraction through following the time- and division-influenced expression of several pro- and anti-apoptotic proteins within CFSE-labeled cultures. Several findings, involving both human and mouse B cells, show that a mitochondria-dependent apoptotic pathway involving p53 contributes to the high AICD susceptibility of replicating blasts. Activated B cell clones exhibit elevated p53 protein and elevated mRNA/protein of pro-apoptotic molecules known to be under direct p53 transcriptional control, Bax, Bad, Puma, Bid, and pro-caspase 6, accompanied by reduced anti-apoptotic Bcl-2. Under these conditions, Bim levels were not increased. Findings that full length Bid protein significantly declines in AICD-susceptible replicating blasts, while Bid mRNA does not, suggests that Bid is actively cleaved to short-lived, pro-apoptotic tBid. AICD was diminished, albeit not eliminated, by p53 siRNA transfection, genetic deletion of p53, or Bcl-2 overexpression. DNA damage is a likely trigger for p53-dependent AICD since susceptible lymphoblasts expressed significantly elevated levels of both phospho-ATMser1980 and phospho-H2AXser139. Deficiency in activation-induced cytosine deaminase (AID) diminishes but does not ablate murine B cell AICD, indicating that AID-induced DNA damage is only in part responsible. Evidence for p53-influenced AICD during this route of TI clonal expansion raises the possibility that progeny bearing p53 mutations might undergo positive selection in peripherally inflamed tissues with elevated levels of IL-4 and BAFF.
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