Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy.
Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy.
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DOI：
10.1172/jci13220
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发表时间：
2001-09
期刊：
影响因子：
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通讯作者：
A. Wells;M. Walsh;J. Bluestone;L. Turka
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文献类型：
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作者：
A. Wells;M. Walsh;J. Bluestone;L. Turka
原始T细胞对TCR结扎和CD28共刺激的增殖反应是令人惊讶的异质性。许多进入G1期的细胞在细胞周期中无法进一步发展，其中一些细胞随后在重新刺激时无法分裂，即使在IL-2存在的情况下也是如此。这种IL-2不可逆的无能不同于在没有CD28共刺激的情况下，TCR占位所引起的IL-2可逆无能。在这里，我们集中在细胞周期进程和共刺激(CD28/CTLA-4)信号在无能调节中的作用。我们表明，CD28共刺激不足以避免无能，激活的T细胞必须在细胞周期中进行，才能逃避无能。诱导这种“分裂-阻止”形式的无能需要在初级反应中使用CTLA-4信号。此外，细胞分裂本身不足以避免无能：少数在CD28共刺激阻断期间经历多轮细胞分裂的T细胞无法逃脱克隆无能的最终诱导。因此，初级T细胞的无能避免是一个多步骤的过程：为了参与有效的免疫反应，通过其抗原受体激活的单个T细胞必须接受CD28共刺激并在细胞周期中进行。无能既可以通过CTLA-4信号和细胞周期进程的失败相结合来诱导，也可以通过一种不依赖于增殖的机制来诱导，在这种机制中，在没有CD28的情况下发生TCR连接。
Primary T cell proliferative responses to TCR ligation plus CD28 costimulation are surprisingly heterogeneous. Many cells that enter G1 fail to progress further through the cell cycle, and some of these cells subsequently fail to divide upon restimulation, even in the presence of IL-2. Such IL-2-refractory anergy is distinct from the IL-2-reversible anergy induced by TCR occupancy in the absence of CD28 costimulation. Here, we focus on the contributions of cell cycle progression and costimulatory (CD28/CTLA-4) signals in the regulation of anergy. We show that CD28 costimulation is not sufficient for anergy avoidance and that activated T cells must progress through the cell cycle in order to escape anergy. Induction of this "division-arrest" form of anergy requires CTLA-4 signaling during the primary response. Also, cell division per se is not sufficient for anergy avoidance: the few T cells that undergo multiple rounds of cell division during overt CD28 costimulatory blockade do not escape the ultimate induction of clonal anergy. Anergy avoidance by primary T cells is thus a multistep process: in order to participate in a productive immune response, an individual T cell activated through its antigen receptor must receive CD28 costimulation and progress through the cell cycle. Anergy may be induced either through a combination of CTLA-4 signaling and the failure of cell cycle progression, or through a proliferation-independent mechanism in which TCR ligation occurs in the absence of CD28.