CD27 and ICOS as Targets of PD‐1/PD‐L1 Signaling to Regulate Resident Memory CD8 + T‐Cell‐Mediated Pulmonary Protection and Pathology

作者：Yuanyuan Chen, Zhenzhen Wang, Zhenzhen Wang, Liqiang Song, Qianqian Chen, Hang Zhang, Tao Pan, Jianli Pan, Sheng Zhao, Ting Shang, Hong’en Xu, Xing Lv, Jing Li, Fei Kang, Yongzhan Nie, Feng Zhao, Lei Shi, Zheng Wang, Zheng Wang · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202512452 · 被引用次数：1 · 研究领域：Nuclear Receptors and Signaling、Cancer Immunotherapy and Biomarkers、Phagocytosis and Immune Regulation

Abstract Tissue‐resident memory CD8 + T cells (T RM cells) provide superior frontline defense against pathogens. While the role of costimulation in effector and memory CD8 + T‐cell development is well characterized, how costimulatory signaling governs CD8 + T RM cells homeostasis at the memory phase remains poorly defined. Here it is revealed that the costimulatory receptors CD27 and ICOS coordinately sustain PD‐1 high CD8 + T RM cell populations following resolution of acute influenza infection. These costimulatory signals serve as critical targets for PD‐1/PD‐L1 blockade, thereby facilitating the rejuvenation of PD‐1 high T RM cells and influencing the progression of fibrotic sequelae during the memory phase. Mechanistic dissection identifies the nuclear receptor Nur77 (NR4A1) as the convergent transcriptional hub downstream of CD27/ICOS, governing proliferative renewal and maintenance of PD‐1 high T RM cells. Therapeutic administration of a CD27 agonist not only amplified this T RM cell subset in late‐stage memory but also conferred cross‐protective immunity against heterosubtypic viral challenges. Clinically, the expressions of CD27 and ICOS are enriched in CD8 + T cells within the lung tissues of patients with pulmonary fibrosis. Collectively, these findings establish the “CD27/ICOS‐NR4A1‐proliferation” axis as a linchpin of PD‐1/PD‐L1‐mediated T RM cell homeostasis, revealing druggable targets for intercepting infection‐associated fibrotic progression.