美国宾夕法尼亚大学E. John Wherry团队发现，LAG-3维持TOX表达并调控CD94/NKG2-Qa-1b轴以控制耗竭CD8 T细胞的NK受体表达和细胞毒性。2024年8月8日出版的《细胞》杂志发表了这项成果。
研究人员表示，在慢性病毒感染和癌症中，耗竭的CD8 T细胞（Tex细胞）具有持续的抑制受体（IR）共表达。通过阻断PD-1等IR可以重新激活Tex细胞，但通过同时靶向多个IR（包括PD-1和LAG-3）可以实现协同的重新激活和增强的疾病控制。
为了揭示这些IR通路被破坏时的内在分子变化，研究人员阐明了PD-1和/或LAG-3缺失对慢性感染期间Tex细胞的影响。这些分析揭示了PD-1和LAG-3在调节Tex细胞增殖和效应功能中的不同作用。
此外，这些研究确定了LAG-3在维持TOX和Tex细胞耐受性中的重要作用，并发现了一个LAG-3依赖的回路，这一回路产生了一个CD94/NKG2+的Tex细胞亚群，其通过识别应激配体Qa-1b介导的细胞毒性增强，类似的观察也在人类中发现。这些分析解开了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。
附：英文原文
Title: LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity
Author: 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
Issue&Volume: 2024/08/08
Abstract: Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitoryreceptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigorationand enhanced disease control can be achieved by co-targeting multiple IRs includingPD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathwaysare 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 andLAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studiesidentified 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-redundantmechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.
DOI: 10.1016/j.cell.2024.07.018
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00778-5