PD-1 and its ligands in ILC2-mediated airway inflammation in asthma: context-dependent mechanisms and therapeutic implications
Abstract
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.
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BibTeX
@article{ma2026ligands,
title = {{PD-1 and its ligands in ILC2-mediated airway inflammation in asthma: context-dependent mechanisms and therapeutic implications}},
author = {Liu Ma and Mingrong Zhang and Shengdong Gou and Qifu He},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1988503},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1988503},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PD-1 and its ligands in ILC2-mediated airway inflammation in asthma: context-dependent mechanisms and therapeutic implications
AU - Liu Ma
AU - Mingrong Zhang
AU - Shengdong Gou
AU - Qifu He
PY - 2026
DA - 2026/11/04
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1988503
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1988503
AB - 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.
SN - 1663-9812
ER -