Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase
Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase
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DOI：
10.1073/pnas.0911573106
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发表时间：
2009-12-01
影响因子：
11.1
通讯作者：
Suh, Woong-Kyung
中科院分区：
文献类型：
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作者：
Gigoux, Mathieu;Shang, Jijun;Suh, Woong-Kyung
T细胞共刺激受体CD 28和诱导型共刺激分子（ICOS）是滤泡B辅助性T细胞（T-FH）和生发中心（GC）反应所必需的。CD 28和ICOS使用的常见信号转导物是磷酸肌醇3-激酶（PI 3 K）。尽管已知CD 28介导的PI 3 K活化对于GC反应是不可或缺的，但ICO驱动的PI 3 K信号传导的作用尚未确定。我们在这里表明，通过ICOS选择性地失去激活PI 3 K的能力的敲入小鼠在T-FH生成、GC反应、抗体类别转换和抗体亲和力成熟方面存在严重缺陷。在预活化的CD 4（+）T细胞中，ICOS传递了一种有效的PI 3 K信号，这对于诱导关键的T-FH细胞因子IL-21和IL-4至关重要。在相同的设置下，CD 28不能激活PI 3 K，但支持T细胞的稳健的二次扩增。因此，我们的研究结果表明，在T-FH的产生中，ICOS-PI 3 K途径的非冗余功能，并表明CD 28和ICOS在T-FH分化的多步骤过程中发挥不同的作用。
The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T-FH) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T-FH generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4(+) T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T-FH cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T-FH and suggest that CD28 and ICOS play differential roles during a multistep process of T-FH differentiation.