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

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.