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

Here it is revealed that the costimulatory receptors CD27 and ICOS are essential for the long‐term maintenance of PD‐1high CD8+ TRM cells following influenza infection. PD‐L1 blockade enhances the proliferation and activation of these cells through Nur77 activation downstream of the CD27/ICOS signaling axis, thereby boosting host immunity against secondary viral challenges while concurrently exacerbating pulmonary fibrosis sequelae. Abstract 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. Here it is revealed that the costimulatory receptors CD27 and ICOS are essential for the long-term maintenance of PD-1 high CD8 + T RM cells following influenza infection. PD-L1 blockade enhances the proliferation and activation of these cells through Nur77 activation downstream of the CD27/ICOS signaling axis, thereby boosting host immunity against secondary viral challenges while concurrently exacerbating pulmonary fibrosis sequelae. 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. Advanced Science, EarlyView.