未磷酸化酪氨酸介导PD-1对T细胞信号凝聚体形成的抑制
未磷酸化酪氨酸介导PD-1对T细胞信号凝聚体形成的抑制
作者： 小柯机器人 发布时间：2026/9/11 19:53:11
本期文章：《科学》：Volume 393 Issue 6816
2026年9月10日，美国基因泰克公司Andrey S. Shaw等科学家在《科学》（Science）发表研究，揭示了未磷酸化酪氨酸介导PD-1抑制T细胞信号凝聚体形成的机制。
T细胞受体（TCR）接合可刺激一种生物分子凝聚体的形成，其中包括支架蛋白活化T细胞连接蛋白（LAT）。研究人员探究了免疫抑制性受体程序性细胞死亡蛋白1（PD-1）是否通过阻碍TCR诱导的LAT凝聚来发挥抑制作用。体外重构显示，PD-1的胞质结构域直接抑制LAT凝聚。这种抑制性相互作用需要PD-1两个抑制基序中的酪氨酸残基。与当前的工作模型相反，酪氨酸磷酸化消除了PD-1的抑制作用。在T细胞中，用色氨酸替换酪氨酸重建了PD-1的抑制作用，证实磷酸化并不介导这一效应。这些发现支持了以下概念：抑制基序中提供氢键的芳香族残基构成了主要机制，可解释抑制性受体如何破坏信号网络并阻断免疫激活。
附：英文原文
Title: Unphosphorylated tyrosines mediate PD-1 inhibition of T cell signaling condensate formation
Author: Monica Sharma, Zachary B. Katz, David C. Dewitt, Kiersten M. Ruff, Akashdip Singh, Huan Lan, Wilson Phung, Jeffery Tom, Aimin Song, Jawahar Sudhamsu, John Davies, John G. Quinn, Rohit V. Pappu, Andrey S. Shaw
Issue&Volume: 2026-09-10
Abstract: T cell receptor (TCR) engagement stimulates formation of a biomolecular condensate, including the scaffold protein linker of activated T cells (LAT). We investigated whether the immune-inhibitory receptor programmed cell death protein 1 (PD-1) inhibits by impeding TCR-induced LAT condensation. In vitro reconstitutions revealed that the cytoplasmic domain of PD-1 directly inhibited LAT condensation. This inhibitory interaction required tyrosine residues in the two inhibitory motifs of PD-1. Contrary to current working models, tyrosine phosphorylation eliminated PD-1 inhibition. Replacing tyrosine with tryptophan reconstituted PD-1 inhibition in T cells, confirming that phosphorylation does not mediate this effect. These findings support the concept that hydrogen bond–donating aromatic residues within inhibitory motifs provide the primary mechanism that explains how inhibitory receptors disrupt signaling networks and block immune activation.
DOI: 10.1126/science.adt9365
Source: https://www.science.org/doi/10.1126/science.adt9365