PDF(Pubmed)
Abstract：
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.
摘要：
慢性病毒感染和癌症中的耗尽的CD8T（Tex）细胞具有抑制受体（IR）的持续共表达。Tex细胞可以通过阻断IR来恢复活力，例如PD-1，但是通过共同靶向包括PD-1和LAG-3在内的多个IR，可以实现协同恢复和增强的疾病控制。为了剖析这些IR通路被破坏时固有的分子变化，我们研究了慢性感染期间PD-1和/或LAG-3丢失对Tex细胞的影响.这些分析揭示了PD-1和LAG-3在调节Tex细胞增殖和效应子功能中的不同作用。分别。此外，这些研究确定了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，该电路产生了Tex细胞的CD94/NKG2亚群，具有通过识别应激配体Qa-1b介导的增强的细胞毒性，在人类中也有类似的观察。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。
