PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation
PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation
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DOI：
10.3389/fimmu.2019.00630
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发表时间：
2019-03-29
影响因子：
7.3
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Mizuno, Reina;Sugiura, Daisuke;Okazaki, Taku
针对程序性细胞死亡 1 (PD-1) 的癌症免疫疗法可激活肿瘤特异性 T 细胞，并为各种癌症提供临床益处。然而，PD-1功能的分子基础仍然是个谜。尤其是，目前还不清楚 PD-1 主要针对哪个信号通路。此外，PD-1在共刺激下抑制T细胞受体（TCR）依赖性T细胞激活的能力也存在争议。在这里，我们使用 T 细胞和抗原呈递细胞的共培养系统，对共受体和配体进行靶向删除和过表达，并检查了 CD28 和 ICOS 共刺激 TCR 刺激后 PD-1 对 T 细胞活化的抑制效力。作为 T 细胞激活的明确标准，我们使用了细胞因子产生能力的获得，这代表了 T 细胞最重要的功能之一。在不存在以及存在 CD28 共刺激的情况下，PD-1 抑制 TCR 刺激后的功能性 T 细胞活化，表明 PD-1 可以直接抑制 TCR 信号。值得注意的是，CD28 共刺激相当削弱了 PD-1 抑制 TCR 依赖性功能性 T 细胞激活的效率。此外，PD-1 通过 ICOS 共刺激抑制 TCR 依赖性功能性 T 细胞活化，与 CD28 共刺激一样有效。此外，我们发现，需要 ICOS 共刺激的抗原诱导的滤泡辅助 T (T-FH) 细胞的维持在体内受到 PD-1 的持续抑制。这些发现表明 PD-1 主要针对 TCR 信号来抑制功能性 T 细胞激活。因此，PD-1 充当 T 细胞激活的变阻器，而不是特定刺激性共受体的抑制剂。
Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (T-FH) cells that required ICOS co-stimulation was persistently restrained by PD-1 in vivo. These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor.