{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T13:22:01Z","timestamp":1794057721502,"version":"4.8.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic obstructive pulmonary disease (COPD) is a significant global health concern, marked by persistent inflammation and immune dysregulation. Although it is widespread and has substantial clinical implications, the systemic immune mechanisms driving disease progression are not fully understood. Since blood contains a diverse array of immune cells and offers a non-invasive means of assessing immune homeostasis and overall physiological status, investigating immune dysregulation through blood sampling offers considerable value for both basic research and clinical application. This approach can provide novel insights into the pathogenesis of COPD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study employed high-dimensional flow cytometry and RNA sequencing to comprehensively characterize peripheral immune cells from a cohort of 69 COPD patients spanning clinical stages 1 to 4, alongside 41 healthy donors as controls. To capture granulocyte populations typically excluded from peripheral blood mononuclear cell analyses, fresh whole blood samples were analyzed directly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our study revealed a marked shift in the myeloid-lymphoid balance, characterized by elevated neutrophils, eosinophils, and classical monocytes that correlated with disease severity, alongside reduced CD8<jats:sup>+<\/jats:sup> T cells and circulating T follicular helper cells. Transcriptional profiling identified oxidative stress pathways, T cell suppression, and aberrant natural killer (NK) cell activation as hallmarks of advanced COPD. Notably, activated Nkp44<jats:sup>+<\/jats:sup> NK cells were significantly enriched in severe stages, implicating their role in perpetuating inflammation. Smoking exacerbated immune perturbations, including upregulated complement activation and B cell pathways, though cessation partially restored transcriptional homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study underscores the value of peripheral immune profiling in capturing the heterogeneity of COPD. The results reveal systemic immune dysregulation-especially NK cell hyperactivity and point to potential therapeutic avenues aimed at modulating immune responses to slow disease progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1623319","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T05:31:13Z","timestamp":1758259873000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Dysregulated NK cell activation and myeloid-lymphoid imbalance underpin COPD progression: insights from high-dimensional immune profiling and smoking-induced immune remodeling"],"prefix":"10.3389","volume":"16","author":[{"given":"Qin","family":"Qiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Qumu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2015.76","article-title":"Chronic obstructive pulmonary disease","volume":"1","author":"Barnes","year":"2015","journal-title":"Nat Rev Dis Prim"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01431","article-title":"Roles of myeloid and lymphoid cells in the pathogenesis of chronic obstructive pulmonary disease","volume":"9","author":"Ni","year":"2018","journal-title":"Front Immunol"},{"key":"B3","first-page":"1","volume-title":"World health statistics 2024:monitoring health for the SDGs, Sustainable Development Goals","year":"2024"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.46598","article-title":"Global burden of chronic obstructive pulmonary disease through 2050","volume":"6","author":"Boers","year":"2023","journal-title":"JAMA Netw Open"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1465-9921-10-53","article-title":"Altered effector function of peripheral cytotoxic cells in COPD","volume":"10","author":"Urbanowicz","year":"2009","journal-title":"Respir Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12931-019-1105-z","article-title":"Multi-level immune response network in mild-moderate Chronic Obstructive Pulmonary Disease (COPD)","volume":"20","author":"Cruz","year":"2019","journal-title":"Respir Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2147\/copd.s1759","article-title":"Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease","volume":"3","author":"Gadgil","year":"2008","journal-title":"Int J COPD"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-68753-1","article-title":"Alteration of immunophenotype of human macrophages and monocytes after exposure to cigarette smoke","volume":"10","author":"da Silva","year":"2020","journal-title":"Sci Rep"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.733324","article-title":"The role of innate lymphoid cells in chronic respiratory diseases","volume":"12","author":"Hsu","year":"2021","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1378\/chest.13-0873","article-title":"Distribution of T-cell subsets in BAL fluid of patients with mild to moderate COPD depends on current smoking status and not airway obstruction","volume":"145","author":"Forsslund","year":"2014","journal-title":"Chest"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2007.03451.x","article-title":"Increased intracellular T helper 1 proinflammatory cytokine production in peripheral blood, bronchoalveolar lavage and intraepithelial T cells of COPD subjects","volume":"150","author":"Hodge","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2020.03.017","article-title":"Eosinophils in COPD\u2014Current concepts and clinical implications","volume":"8","author":"Mycroft","year":"2020","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2020-215167","article-title":"Eosinophilic inflammation in COPD: From an inflammatory marker to a treatable trait","volume":"76","author":"David","year":"2021","journal-title":"Thorax"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12931-020-01436-7","article-title":"Blood neutrophil counts are associated with exacerbation frequency and mortality in COPD","volume":"21","author":"Lonergan","year":"2020","journal-title":"Respir Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200703-456SO","article-title":"Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary","volume":"176","author":"Rabe","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00861","article-title":"UMAP: uniform manifold approximation and projection","volume":"3","author":"McInnes","year":"2018","journal-title":"J Open Source Softw"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22837","article-title":"flowClean: Automated identification and removal of fluorescence anomalies in flow cytometry data","volume":"89","author":"Fletez-Brant","year":"2016","journal-title":"Cytom Part A J Int Soc Anal Cytol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw191","article-title":"FlowAI: Automatic and interactive anomaly discerning tools for flow cytometry data","volume":"32","author":"Monaco","year":"2016","journal-title":"Bioinformatics"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22625","article-title":"FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data","volume":"87","author":"Van Gassen","year":"2015","journal-title":"Cytom Part A"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0294236","article-title":"SRplot: A free online platform for data visualization and graphing","volume":"18","author":"Tang","year":"2023","journal-title":"PloS One"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2015.084","article-title":"Usefulness of neutrophil to lymphocyte ratio in patients with chronic obstructive pulmonary disease: A prospective observational study","volume":"31","author":"Lee","year":"2016","journal-title":"Korean J Intern Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02035","article-title":"Human monocyte subsets and phenotypes in major chronic inflammatory diseases","volume":"10","author":"Kapellos","year":"2019","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01263","article-title":"NK cells in the human lungs","volume":"10","author":"Hervier","year":"2019","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1084\/jem.20101499","article-title":"Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+CD27+CD43+CD70-","volume":"208","author":"Griffin","year":"2011","journal-title":"J Exp Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.04.011","article-title":"Innate immune reprogramming in circulating neutrophils of COPD patients","volume":"156","author":"Mariotti","year":"2025","journal-title":"J Allergy Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.154.5.8912739","article-title":"Integrin upregulation on sputum neutrophils in smokers with chronic airway obstruction","volume":"154","author":"Maestrelli","year":"1996","journal-title":"Am J Respir Crit Care Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1556992","article-title":"Multifaceted, unique role of CD11c in leukocyte biology","volume":"16","author":"Hou","year":"2025","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.5603\/ARM.a2017.0045","article-title":"Eosinophilic COPD \u2014 A distinct phenotype of the disease","volume":"85","author":"Tworek","year":"2017","journal-title":"Adv Respir Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1177\/2040622315609251","article-title":"Eosinophilic airway inflammation: Role in asthma and chronic obstructive pulmonary disease","volume":"7","author":"George","year":"2016","journal-title":"Ther Adv Chronic Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2013.09.010","article-title":"The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma","volume":"64","author":"Pappas","year":"2013","journal-title":"Cytokine"},{"key":"B32","doi-asserted-by":"publisher","first-page":"464","DOI":"10.3390\/antiox11030464","article-title":"The emerging role of macrophages in chronic obstructive pulmonary disease: the potential impact of oxidative stress and extracellular vesicle on macrophage polarization and function","volume":"11","author":"Finicelli","year":"2022","journal-title":"Antioxidants"},{"key":"B33","doi-asserted-by":"publisher","first-page":"298","DOI":"10.7150\/ijms.100160","article-title":"Advances on the role of lung macrophages in the pathogenesis of chronic obstructive pulmonary disease in the era of single-cell genomics","volume":"22","author":"Li","year":"2025","journal-title":"Int J Med Sci"},{"key":"B34","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.immuni.2020.12.003","article-title":"Distinct developmental pathways from blood monocytes generate human lung macrophage diversity","volume":"54","author":"Evren","year":"2021","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","first-page":"R61","DOI":"10.1186\/cc8959","article-title":"Differential down-regulation of HLA-DR on monocyte subpopulations during systemic inflammation","volume":"14","author":"Kim","year":"2010","journal-title":"Crit Care"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0010020","article-title":"Characterization of T lymphocytes in chronic obstructive pulmonary disease","volume":"1","author":"Barnes","year":"2004","journal-title":"PloS Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3724\/abbs.2021009","article-title":"The functions of CD4 T-helper lymphocytes in chronic obstructive pulmonary disease","volume":"54","author":"Qin","year":"2022","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jaci.2016.05.011","article-title":"Inflammatory mechanisms in patients with chronic obstructive pulmonary disease","volume":"138","author":"Barnes","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.160.2.9812020","article-title":"CD8 +ve cells in the lungs of smokers with chronic obstructive pulmonary disease","volume":"160","author":"Saetta","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12931-018-0940-7","article-title":"Cytotoxic lymphocytes in COPD airways: Increased NK cells associated with disease, iNKT and NKT-like cells with current smoking","volume":"19","author":"Eriksson Str\u00f6m","year":"2018","journal-title":"Respir Res"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.666045","article-title":"NK cells in the pathogenesis of chronic obstructive pulmonary disease","volume":"12","author":"Rao","year":"2021","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1843.2012.02287.x","article-title":"Enhanced cytotoxic function of natural killer and natural killer T-like cells associated with decreased CD94 (Kp43) in the chronic obstructive pulmonary disease airway","volume":"18","author":"Hodge","year":"2013","journal-title":"Respirology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0058556","article-title":"Differential activation of killer cells in the circulation and the lung: A study of current smoking status and chronic obstructive pulmonary disease (COPD)","volume":"8","author":"Wang","year":"2013","journal-title":"PLoS One"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201712-2513OC","article-title":"Lung dendritic cells drive natural killer cytotoxicity in chronic obstructive pulmonary disease via IL-15Ra","volume":"198","author":"Finch","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13613","article-title":"Impacts of cigarette smoking on immune responsiveness: Up and down or upside down","volume":"8","author":"Qiu","year":"2017","journal-title":"Oncotarget"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903654","article-title":"Chronic cigarette smoke exposure primes NK cell activation in a mouse model of chronic obstructive pulmonary disease","volume":"184","author":"Motz","year":"2010","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1623319\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T05:31:15Z","timestamp":1758259875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1623319\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,19]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2025.1623319"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1623319","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,19]]},"article-number":"1623319"}}