T-cell-intrinsic and -extrinsic regulation of PD-1 function
T-cell-intrinsic and -extrinsic regulation of PD-1 function
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PD-1 功能的 T 细胞内在和外在调节
DOI：
10.1093/intimm/dxab077
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发表时间：
2021
影响因子：
4.4
通讯作者：
Okazaki Taku
中科院分区：
文献类型：
--
作者：
Sugiura Daisuke;Shimizu Kenji;Maruhashi Takumi;Okazaki Il-mi;Okazaki Taku
靶向PD-1（程序性细胞死亡1）的癌症免疫疗法旨在通过激活肿瘤特异性T细胞来破坏肿瘤，否则这些T细胞会被PD-1灭活。尽管这些疗法显著改善了不同癌症类型患者的预后，并彻底改变了癌症治疗，但目前只有有限比例的患者受益于这些疗法。因此，仍然需要破译PD-1的复杂生物学，以提高治疗效果并预防免疫相关的不良事件。特别是，PD-1功能的时空背景和受PD-1抑制的T细胞的特性仅被模糊地理解。我们最近发现，PD-1功能在T细胞应答的活化阶段受到抗原呈递细胞上PD-L1和CD 80的膜相互作用的严格限制，这对于诱导最佳T细胞应答至关重要。我们还发现，T细胞对PD-1作用的敏感性基本上是由T细胞内在因子决定的。在携带对抗原肽具有较低亲和力的T细胞抗原受体（TCR）的T细胞中，PD-1更有效地抑制TCR诱导型基因的表达;从而PD-1优先抑制低亲和力T细胞。因此，PD-1功能由各种T细胞内在和外在因素协调调节，这些因素改变T细胞的反应性和PD-1配体的可用性。对PD-1调控机制的准确和深入理解有望促进有效和安全的免疫疗法的合理开发。
Cancer immunotherapies that target PD-1 (programmed cell death 1) aim to destroy tumors by activating tumor-specific T cells that are otherwise inactivated by PD-1. Although these therapies have significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment, only a limited proportion of patients benefits from the therapies currently. Therefore, there is a continued need to decipher the complex biology of PD-1 to improve therapeutic efficacies as well as to prevent immune-related adverse events. Especially, the spaciotemporal context in which PD-1 functions and the properties of T cells that are restrained by PD-1 are only vaguely understood. We have recently revealed that PD-1 function is strictly restricted at the activation phase of T-cell responses by thecis-interactions of PD-L1 and CD80 on antigen-presenting cells, which is critical for the induction of optimal T-cell responses. We also found that the sensitivity to the effects of PD-1 in T cells is essentially determined by T-cell-intrinsic factors. In T cells bearing T-cell antigen-receptors (TCRs) with lower affinity to antigenic peptides, PD-1 inhibits the expression of TCR-inducible genes more efficiently; thereby PD-1 preferentially suppresses low-affinity T cells. Thus, PD-1 function is coordinately regulated by various T-cell-intrinsic and -extrinsic factors that alter the responsiveness of T cells and the availability of PD-1 ligands. Precise and deeper understanding of the regulatory mechanisms of PD-1 is expected to facilitate the rational development of effective and safe immunotherapies.