CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p 110 heterodimer
CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p 110 heterodimer
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DOI：
10.1182/blood-2007-08-108050
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Okkenhaug, Klaus
中科院分区：
文献类型：
--
作者：
Garcon, Fabien;Patton, Daniel T.;Okkenhaug, Klaus
PI3K活化是T细胞与抗原提呈细胞(APC)结合后观察到的最早的信号事件之一。相关的PI3K催化亚型和TCR和CD28对免疫突触PI3K活性的相对贡献尚未明确确定。使用基于定量成像的分析方法，我们发现T细胞-APC接触区的PI3K活性依赖于PI3K的p110增量，而不是PI3K的p110伽马亚型。CD28独立于其YMNM PI3K招募基序促进T细胞突触产生PIP3，而YMNM PI3K招募基序是有效招募PKC theta所必需的。CD28可以部分弥补T细胞活化过程中p110 Delta活性的缺失，这表明CD28和p110 Delta是平行和互补的激活T细胞的途径。与此一致的是，CD28和p110 Delta双缺陷小鼠的免疫功能严重受损。因此，我们认为联合靶向p110 Delta活性和CD28共刺激具有潜在的治疗潜力。
Activation of PI3K is among the earliest signaling events observed in T cells after conjugate formation with antigen-presenting cells (APCs). The relevant PI3K catalytic isoform and relative contribution of the TcR and CD28 to PI3K activity at the immune synapse have not been determined unequivocally. Using a quantitative imaging-based assay, we show that the PI3K activity at the T cell-APC contact area is dependent on the p110 delta, but not the p110 gamma, isoform of PI3K. CD28 enhanced PIP3 production at the T-cell synapse independently of its YMNM PI3K-recruitment motif that instead was required for efficient PKC theta recruitment. CD28 could partially compensate for the lack of p110 delta activity during T-cell activation, which indicates that CD28 and p110 delta act in parallel and complementary pathways to activate T cells. Consistent with this, CD28 and p110 delta double-deficient mice were severely immune compromised. We therefore suggest that combined pharmaceutic targeting of p110 delta activity and CD28 costimulation has potent therapeutic potential.