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

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.