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 (TRM 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+ TRM cells homeostasis at the memory phase remains poorly defined. Here it is revealed that the costimulatory receptors CD27 and ICOS coordinately sustain PD-1high CD8+ TRM 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-1high TRM 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-1high TRM cells. Therapeutic administration of a CD27 agonist not only amplified this TRM 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 TRM cell homeostasis, revealing druggable targets for intercepting infection-associated fibrotic progression.