CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression
CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression
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DOI：
10.4049/jimmunol.164.1.144
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发表时间：
2000-01-01
影响因子：
4.4
通讯作者：
Boussiotis, VA
中科院分区：
文献类型：
--
作者：
Appleman, LJ;Berezovskaya, A;Boussiotis, VA
在存在通过Ag的TCR连接的情况下，CD 28途径介导用于T细胞活化、细胞因子分泌和T细胞扩增的最有效的共刺激信号。尽管由于IL-2分泌和随后经由IL-2受体的信号传导，CD 28共刺激促进T细胞扩增，最近的研究表明，在CTLA 4缺陷型小鼠中通过无对抗的CD 28刺激介导的显著的T细胞扩增是IL-2非依赖性的。因此，我们试图剖析CD 28和IL-2受体途径对细胞周期进程的影响，并确定CD 28途径调节T细胞扩增的分子机制，我们发现，CD 28共刺激以IL-2非依赖性方式直接调节T细胞周期进入和G（1）期进展，导致细胞周期蛋白D2相关的cdk 4/cdk 6和细胞周期蛋白E相关的cdk 4/cdk 6活化。相关cdk 2.随后进入S期的进程是通过IL-2依赖性和IL-2非依赖性机制介导的，尽管在缺乏IL-2的情况下，大多数T细胞在G（1）/S转变时被阻滞，但它们中的相当一部分进入S期。细胞周期蛋白-cdk复合物激活和细胞周期进程的关键调节机制是p27（kip 1）cdk抑制剂的下调，其在转录后水平上通过其在蛋白酶体途径中的泛素依赖性降解介导。因此，CD 28共刺激以IL-2非依赖性和IL-2依赖性方式介导T细胞扩增，并在两个不同点调节细胞周期进程：在G（1）早期和G（1）/S转换期。
In the presence of TCR ligation by Ag, CD28 pathway mediates the most potent costimulatory signal for T cell activation, cytokine secretion, and T cell expansion, Although CD28 costimulation promotes T cell expansion due to IL-2 secretion and subsequent signaling via the IL-2 receptor, recent studies indicate that the dramatic T cell expansion mediated through the unopposed CD28 stimulation in CTLA4-deficient mice is IL-2 independent. Therefore, we sought to dissect the effects of CD28 and IL-2 receptor pathways on cell cycle progression and determine the molecular mechanisms by which the CD28 pathway regulates T cell expansion, Here we show that CD28 costimulation directly regulates T cell cycle entry and progression through the G(1) phase in an IL-2-independent manner resulting in activation of cyclin D2-associated cdk4/cdk6 and cyclin E-associated cdk2. Subsequent progression into the S phase is mediated via both IL-2-dependent and IL-2-independent mechanisms and, although in the absence of IL-2 the majority of T cells are arrested at the G(1)/S transition, a significant fraction of them progresses into the S phase. The key regulatory mechanism for the activation of cyclin-cdk complexes and cell cycle progression is the down-regulation of p27(kip1) cdk inhibitor, which is mediated at the posttranscriptional level by its ubiquitin-dependent degradation in the proteasome pathway Therefore, CD28 costimulation mediates T cell expansion in an IL-2-independent and IL-2 dependent manner and regulates cell cycle progression at two distinct points: at the early G(1) phase and at the G(1)/S transition.