共抑制性PD-1（编程死亡-1）信号通路在肿瘤特异性T细胞反应中起到重要作用。然而，它也对外周耐受的维持有贡献，因为接受抗-PD-1治疗的患者易于发生免疫相关不良事件。尽管如此，PD-1/PDL-1轴在T细胞稳态下的生理作用仍不明确。本研究发现，在稳态条件下，PD-1信号的缺失导致肝脏的CD8+ T细胞优先扩增。这些细胞表现为寡克隆T细胞受体（TCR）亚群和终末分化疲劳状态。转录因子EOMES对克隆扩增和这一分化程序的获取是必需的。最后，单细胞转录组学结合TCR亚群分析支持这些细胞细胞起源于肝脏驻留记忆CD8+ T细胞。总体而言，我们展示了PD-1信号在肝脏记忆T细胞稳态中的作用。 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

The co-inhibitory programmed death (PD)-1 signaling pathway plays a major role in the context of tumor-specific T cell responses. Conversely, it also contributes to the maintenance of peripheral tolerance, as patients receiving anti-PD-1 treatment are prone to developing immune-related adverse events. Yet, the physiological role of the PD-1/PDL-1 axis in T cell homeostasis is still poorly understood. Herein, we show that under steady-state conditions, the absence of PD-1 signaling led to a preferential expansion of CD8+ T cells in the liver. These cells exhibit an oligoclonal T cell receptor (TCR) repertoire and a terminally differentiated exhaustion profile. The transcription factor EOMES is required for the clonal expansion and acquisition of this differentiation program. Finally, single-cell transcriptomics coupled with TCR repertoire analysis support the notion that these cells arise locally from liver-resident memory CD8+ T cells. Overall, we show a role for PD-1 signaling in liver memory T cell homeostasis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.