Exploration of the Role and Mechanism of NK Cell Surface Receptor CD96 in Chronic Obstructive Pulmonary Disease
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.Results:In patients with COPD, the proportion of peripheral blood CD96+ NK cells exhibited a positive correlation with the duration of hospital stays, CAT scores, and the incidence of acute exacerbations occurring two or more times within one year. Single-cell RNA sequencing of mouse pulmonary CD45+ immune cells demonstrated enhanced communication among pulmonary immune cells and abnormal activation of the CD96 pathway following exposure to cigarette smoke. Flow cytometry analysis of lung tissue from cigarette smoke-exposed mice revealed an increased proportion of CD96+ NK cells, along with enhanced CD155 signaling as quantified by immunofluorescence in lung tissue. This was accompanied by a decrease in FEV0.2/FVC, emphysematous structural destruction, collagen deposition, airway wall thickening, and upregulation of several inflammatory mediators, including IL-17A, IFN-gamma, IL-6, and TNF-alpha. Intervention with anti-CD96 monoclonal antibodies partially improved lung function, reduced alveolar damage, collagen deposition, and airway remodeling, downregulated IL-17A and various pro-inflammatory cytokine levels, and exerted a protective effect on the maintenance of IFN-gamma-producing capacity in NK cells, achieving a relative balance between anti-inflammatory effects and the preservation of essential immune functions. The synchronous upregulation of CD96 and SHIP1 in NK cells, along with functional improvement following CD96 blockade, suggests the potential existence of a CD96-SHIP1-related inhibitory pathway that impairs NK cell function by diminishing IFN-gamma secretion and promotes Th17/IL-17A-mediated chronic inflammation involved in the disease process.Conclusion:The NK cell surface receptor CD96 is correlated with disease severity and chronic inflammatory status in COPD, suggesting that CD96+ NK cells may function as potential prognostic markers for this condition. Anti-CD96 intervention has been shown to mitigate CS-induced lung injury in mice, downregulate the Th17/IL-17A pathway, and associate NK cell dysfunction with Th1/Th17 imbalance. The strategy of targeting CD96 offers a novel approach to reduce inflammation, protect lung function, and decrease the frequency of acute exacerbations. Future studies should further investigate its potential for clinical translation in COPD patients and integrate multi-omics technologies into its regulatory network, thereby providing a more comprehensive molecular foundation for precise treatment.