Role of NK surface inhibitory receptor CD96 in chronic obstructive pulmonary disease and the effect of targeted CD96 intervention

Background CD96 is an inhibitory receptor found on natural killer (NK) cells, yet its mechanism of action in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to examine the alterations and function of CD96 in COPD and to assess the impact of anti-CD96 intervention. Methods Peripheral blood samples were obtained from 44 patients with chronic obstructive pulmonary disease (COPD), along with a cigarette smoke (CS)-induced COPD mouse model. The expression of CD96 and IFN-γ in natural killer (NK) cells was measured using flow cytometry. Lung function, histopathological changes, airway remodeling, and levels of inflammatory mediators were evaluated in mice following 6 or 12 weeks of CS exposure, with or without the administration of anti-CD96 antibody. Results In patients with COPD, the expression of CD96 on NK cells was elevated, and the proportion of CD96⁺NK cells showed a positive correlation with the duration of hospitalization, CAT scores, and the incidence of acute exacerbations (≥ 2) within one year. In mice exposed to cigarette smoke, increased signaling through CD96 and CD155 was associated with a reduction in the FEV0.2/FVC ratio, disruption of emphysema-like structures, collagen deposition, airway wall thickening, and the upregulation of various inflammatory mediators, including IL-17A, IFN-γ, IL-6, and TNF-α. Treatment with anti-CD96 partially restored lung function, reduced alveolar injury, collagen deposition, and airway remodeling, and downregulated IL-17A along with several pro-inflammatory cytokines. Furthermore, this treatment preserved the IFN-γ production capacity of NK cells. The concurrent upregulation of CD96 and SHIP1 in NK cells, along with the enhancement of their function following CD96 blockade, suggests the involvement of a CD96-SHIP1-related inhibitory pathway in the disease process. Conclusion CD96-overexpressing NK cells and CD96/SHIP1-associated signaling are associated with disease severity and a chronic inflammatory state in COPD. The anti-CD96 intervention mitigated CS-induced lung injury in mice, indicating that CD96 may serve as a novel target for immunotherapy in COPD. Future research should further investigate its clinical translational potential in COPD patients and analyze its regulatory network by integrating multi-omics technology, thereby providing a more comprehensive molecular foundation for precision therapy.