LAG-3 维持 TOX 表达并调节 CD94/NKG2-Qa-1b 轴，以控制耗竭的 CD8 T 细胞 NK 受体表达和细胞毒性。
LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.
发表日期：2024 Aug 08
作者：
Shin Foong Ngiow, Sasikanth Manne, Yinghui Jane Huang, Tarek Azar, Zeyu Chen, Divij Mathew, Qingzhou Chen, Omar Khan, Jennifer E Wu, Victor Alcalde, Ahron J Flowers, Sean McClain, Amy E Baxter, Makoto Kurachi, Junwei Shi, Alexander C Huang, Josephine R Giles, Arlene H Sharpe, Dario A A Vignali, E John Wherry
来源：
CELL
摘要：
慢性病毒感染和癌症中耗尽的 CD8 T (Tex) 细胞持续共表达抑制性受体 (IR)。 Tex 细胞可以通过阻断 IR（例如 PD-1）来重振活力，但可以通过共同靶向包括 PD-1 和 LAG-3 在内的多种 IR 来实现协同重振和增强疾病控制。为了剖析这些 IR 通路被破坏时内在的分子变化，我们研究了慢性感染期间 PD-1 和/或 LAG-3 的丢失对 Tex 细胞的影响。这些分析揭示了 PD-1 和 LAG-3 分别在调节 Tex 细胞增殖和效应器功能中的不同作用。此外，这些研究还确定了 LAG-3 在维持 TOX 和 Tex 细胞耐久性方面的重要作用，以及 LAG-3 依赖性电路，该电路产生 Tex 细胞的 CD94/NKG2 子集，通过识别应激配体 Qa 介导细胞毒性增强-1b，在人类中也有类似的观察结果。这些分析阐明了 PD-1 和 LAG-3 的非冗余机制及其在调节 Tex 细胞中的协同作用。版权所有 © 2024 Elsevier Inc. 保留所有权利。
Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.Copyright © 2024 Elsevier Inc. All rights reserved.