CD27 and ICOS as targets of PD-1/PD-L1 signaling to regulate resident memory CD8+ T cells mediated pulmonary protection and pathology

While tissue-resident memory CD8+ T cells (TRM cells) provide superior frontline defense against pathogens, the molecular mechanisms governing their persistence and functional regulation remain poorly defined. Our study reveals 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 expression of CD27 and ICOS is enriched in CD8+ T cells within the lung tissues of patients with pulmonary fibrosis. Collectively, our 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.