PD-1 and its ligands in ILC2-mediated airway inflammation in asthma: context-dependent mechanisms and therapeutic implications

Group 2 innate lymphoid cells (ILC2s) contribute to type 2 asthma through rapid production of interleukin-5 and interleukin-13, but the inhibitory pathways that restrain pathogenic ILC2 activity remain incompletely defined. Most evidence for programmed cell death protein 1 (PD-1)-mediated inhibition of ILC2s comes from murine models, humanized mice, and stimulated or expanded human cells; cell-resolved expression and functional engagement of PD-1 have not been established in freshly isolated airway ILC2s from well-characterized asthma cohorts. In available experimental systems, PD-1 engagement suppresses ILC2 proliferation and cytokine production, whereas programmed death-ligand 1 (PD-L1) displayed by ILC2s can act outwardly on PD-1-positive CD4-positive T cells. Programmed death-ligand 2 (PD-L2) can inhibit isolated ILC2s through PD-1, but its whole-lung effects also involve dendritic-cell IL-12 regulation and RGMb-dependent respiratory tolerance. Interpretation therefore depends on the ligand-bearing and responding cells, ligand form, tissue compartment, disease stage, and asthma endotype. This review examines cell-intrinsic PD-1 signaling, ligand-specific cellular interactions, immunometabolic regulation, and translational constraints. The current evidence supports preclinical investigation rather than clinical readiness; direct validation in human airway ILC2s, definition of receptor-proximal signaling, and a predictive biomarker are prerequisites for therapeutic development.