{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:43:55Z","timestamp":1792068235938,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam & Disease"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Immunosenescence demonstrates marked sexual dimorphism, yet the dynamic changes in lymphocyte subsets across the female menopausal transition are poorly defined. This study characterized these age\u2010 and sex\u2010related immune variations in a large Chinese cohort.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n In this cross\u2010sectional study, we analyzed 4209 healthy adults using flow cytometry to quantify lymphocyte subsets and PD\u20101 expression. Females were stratified by age and reproductive stage. Sex comparisons were performed after propensity score age\u2010matching.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Analysis of the female cohort revealed dynamic immune shifts during the menopausal transition, characterized by a \u201cscissor\u2010like\u201d pattern: CD3\n +<\/jats:sup>\n CD4\n +<\/jats:sup>\n T cells (%) and the CD4\/CD8 ratio peaked at 55\u201359 years, while CD3\n +<\/jats:sup>\n CD8\n +<\/jats:sup>\n T cells (%) declined continuously (all\n p<\/jats:italic>\n \u2009<\u20090.001). Notably, CD19\n +<\/jats:sup>\n B cells (%) increased with age in females but decreased in males. After age\u2010matching, pronounced sexual dimorphism was confirmed: females exhibited significantly higher levels of CD3\n +<\/jats:sup>\n T cells, CD3\n +<\/jats:sup>\n CD4\n +<\/jats:sup>\n T cells, CD19\n +<\/jats:sup>\n B cells, NK cells, and CD4\/CD8 ratio, alongside lower PD\u20101 expression on CD4\n +<\/jats:sup>\n T cells and NK cells (all\n p<\/jats:italic>\n \u2009<\u20090.001). In contrast, PD\u20101 expression on CD8\n +<\/jats:sup>\n T cells was higher in females (\n p<\/jats:italic>\n \u2009<\u20090.001).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n These findings suggest that the perimenopausal period represents a key phase of immune remodeling in women, and support the integration of sex and reproductive stage into future immunosenescence research and clinical strategies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/iid3.70558","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:44:52Z","timestamp":1792064692000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic Shifts in Lymphocyte Subsets During the Menopausal Transition and Sexual Dimorphism in Immunosenescence"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8850-0111","authenticated-orcid":false,"given":"Ci","family":"Xuan","sequence":"first","affiliation":[{"name":"Department of Blood Transfusion The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5768-0999","authenticated-orcid":false,"given":"Li","family":"He","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7713-6093","authenticated-orcid":false,"given":"Zhou","family":"Bohan","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6792-9297","authenticated-orcid":false,"given":"Xu","family":"Junming","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Qingchao","sequence":"additional","affiliation":[{"name":"Nanjing Southeast Research Institute Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2582-2687","authenticated-orcid":false,"given":"Huang","family":"Junting","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China"},{"name":"Department of Emergency Medicine, Loudi Hospital The First Affiliated Hospital of Guangzhou Medical University Loudi Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1749-6632.2000.tb06651.x","article-title":"Inflamm\u2010Aging: An Evolutionary Perspective on Immunosenescence","volume":"908","author":"Franceschi C.","year":"2000","journal-title":"Annals of the New York Academy of Sciences"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"318","DOI":"10.3389\/fimmu.2019.00318","article-title":"B Cell Dysfunction Associated With Aging and Autoimmune Diseases","volume":"10","author":"Ma S.","year":"2019","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.arr.2021.101422","article-title":"Immunosenescence and Inflammaging in the Aging Process: Age\u2010Related Diseases or Longevity?","volume":"71","author":"Santoro A.","year":"2021","journal-title":"Ageing Research Reviews"},{"issue":"1","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41590-017-0006-x","article-title":"The Twilight of Immunity: Emerging Concepts in Aging of the Immune System","volume":"19","author":"Nikolich\u2010\u017dugich J.","year":"2018","journal-title":"Nature Immunology"},{"issue":"6","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00391-025-02496-4","article-title":"Ver\u00e4nderungen des Immunsystems im Alter: Immunseneszenz und Auswirkungen auf Impfungen","volume":"58","author":"Weinberger B.","year":"2025","journal-title":"Zeitschrift f\u00fcr Gerontologie und Geriatrie"},{"issue":"8","key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.molmed.2025.01.005","article-title":"A Researcher's Guide to Studying Sex Differences in Immune Aging","volume":"31","author":"Baker C.","year":"2025","journal-title":"Trends in Molecular Medicine"},{"issue":"1","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12979-025-00521-z","article-title":"The Aging Immune System and All\u2010Cause Mortality in Older Americans: Differences Across Sex and Race\/Ethnicity","volume":"22","author":"Duchowny K. A.","year":"2025","journal-title":"Immunity & Ageing: IA"},{"issue":"7","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","DOI":"10.1002\/iid3.70186","article-title":"Disparities in Seasonal Influenza Vaccination in Europe","volume":"13","author":"Giezeman\u2010Smits K. M.","year":"2025","journal-title":"Immunity, Inflammation and Disease"},{"issue":"3","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.yfrne.2014.04.004","article-title":"Gender Differences in Autoimmune Disease","volume":"35","author":"Ngo S. T.","year":"2014","journal-title":"Frontiers in Neuroendocrinology"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/bs.vh.2020.12.015","article-title":"Taneja V: Sexual Dimorphism, Aging and Immunity","volume":"115","year":"2021","journal-title":"Vitamins and Hormones"},{"issue":"1","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41467-020-14396-9","article-title":"Sexual\u2010Dimorphism in Human Immune System Aging","volume":"11","author":"M\u00e1rquez E. J.","year":"2020","journal-title":"Nature Communications"},{"issue":"3","key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.4103\/jmh.jmh_75_25","article-title":"Estrogen and Metabolism: Navigating Hormonal Transitions From Perimenopause to Postmenopause","volume":"16","author":"Patel P.","year":"2025","journal-title":"Journal of Mid\u2010Life Health"},{"issue":"1","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s42977-025-00291-1","article-title":"Sex Hormones and Gender Differences in Immune Responses and Anticancer Immunity: A Comprehensive Review","volume":"77","author":"Roy S.","year":"2026","journal-title":"Biologia Futura"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.3389\/fimmu.2018.02279","article-title":"Sex Hormones in Acquired Immunity and Autoimmune Disease","volume":"9","author":"Moulton V. R.","year":"2018","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jri.2021.103346","article-title":"Menopause Is An Inflection Point of Age\u2010Related Immune Changes in Women","volume":"146","author":"Han A.","year":"2021","journal-title":"Journal of Reproductive Immunology"},{"issue":"4","key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/gme.0b013e31824d8f40","article-title":"Executive Summary of the Stages of Reproductive Aging Workshop + 10: Addressing the Unfinished Agenda of Staging Reproductive Aging","volume":"19","author":"Harlow S. D.","year":"2012","journal-title":"Menopause"},{"issue":"11","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1515\/cclm-2024-0371","article-title":"Within\u2010 and Between\u2010Subject Biological Variation Estimates for the Enumeration of Lymphocyte Deep Immunophenotyping and Monocyte Subsets","volume":"62","author":"Guo K.","year":"2024","journal-title":"Clinical Chemistry and Laboratory Medicine (CCLM)"},{"issue":"1","key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.5114\/ceji.2024.136371","article-title":"Reference Values of Lymphocyte Subsets From Healthy Polish Adults","volume":"49","author":"Roszczyk A.","year":"2024","journal-title":"Central European Journal of Immunology"},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","DOI":"10.31744\/einstein_journal\/2023AO0291","article-title":"Determining Reference Ranges for Immunological Cells of Healthy Indigenous Individuals From a Region in Brazil","volume":"21","author":"Morais I. R. B.","year":"2023","journal-title":"Einstein (S\u00e3o Paulo)"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1599515","article-title":"Decoupled Dynamics of Absolute and Relative Lymphocyte Counts and Age\u2010Polarized CD4(+)\/CD8(+) Ratio in Infants Versus Older Adults","volume":"16","author":"Ge T.","year":"2025","journal-title":"Frontiers in Immunology"},{"issue":"3","key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1080\/15321819.2020.1728543","article-title":"Moroccan Lymphocyte Subsets Reference Ranges: Age, Gender, Ethnicity, and Socio\u2010Economic Factors Dependent Differences","volume":"41","author":"Sahmoudi K.","year":"2020","journal-title":"Journal of Immunoassay and Immunochemistry"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","DOI":"10.1590\/1414-431x2025e14956","article-title":"Establishing the Reference Intervals for Subpopulations of T Lymphocytes, B Lymphocytes, and Natural Killer Cells: Insight From the Brazilian Longitudinal Study of Adult Health (ELSA\u2010Brasil)","volume":"58","author":"Dias I. C. S.","year":"2025","journal-title":"Brazilian Journal of Medical and Biological Research"},{"issue":"13","key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"10985","DOI":"10.18632\/aging.205985","article-title":"An Updated Immunosenescence Exploration in Healthy Chinese Donors: Circular Elevated PD\u20101 on T Cell and Increased Ki67 on CD8+ T Cell Towards Aging","volume":"16","author":"Chang Y.","year":"2024","journal-title":"Aging"},{"issue":"1","key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.imlet.2014.11.003","article-title":"Determination of Lymphocyte Subset Reference Ranges in Peripheral Blood of Healthy Adults by a Dual\u2010Platform Flow Cytometry Method","volume":"163","author":"Rudolf\u2010Oliveira R. C. M.","year":"2015","journal-title":"Immunology Letters"},{"issue":"5","key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"848","DOI":"10.18632\/aging.100894","article-title":"Aging of Immune System: Immune Signature From Peripheral Blood Lymphocyte Subsets in 1068 Healthy Adults","volume":"8","author":"Qin L.","year":"2016","journal-title":"Aging"},{"issue":"7","key":"e_1_2_9_27_1","doi-asserted-by":"crossref","DOI":"10.1177\/0300060520913149","article-title":"Characteristics of and Reference Ranges for Peripheral Blood Lymphocytes and CD4+ T Cell Subsets in Healthy Adults in Shanxi Province, North China","volume":"48","author":"Xu D.","year":"2020","journal-title":"Journal of International Medical Research"},{"issue":"1","key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12865-021-00474-0","article-title":"Reference Ranges of T Lymphocyte Subsets by Single\u2010Platform Among Healthy Population in Southwest China","volume":"22","author":"Wei B.","year":"2021","journal-title":"BMC Immunology"},{"key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.3389\/fimmu.2018.01931","article-title":"Sex Hormones Determine Immune Response","volume":"9","author":"Taneja V.","year":"2018","journal-title":"Frontiers in Immunology"},{"issue":"9","key":"e_1_2_9_30_1","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/j.immuni.2022.07.016","article-title":"Androgen Receptor\u2010Mediated CD8(+) T Cell Stemness Programs Drive Sex Differences in Antitumor Immunity","volume":"55","author":"Yang C.","year":"2022","journal-title":"Immunity"},{"issue":"3","key":"e_1_2_9_31_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/acel.12326","article-title":"How Sex and Age Affect Immune Responses, Susceptibility to Infections, and Response to Vaccination","volume":"14","author":"Giefing\u2010Kr\u00f6ll C.","year":"2015","journal-title":"Aging Cell"},{"key":"e_1_2_9_32_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1570565","article-title":"Toward Understanding Sexual Immune Dimorphism in Humans","volume":"16","author":"Nowak T. J.","year":"2025","journal-title":"Frontiers in Immunology"},{"issue":"7","key":"e_1_2_9_33_1","doi-asserted-by":"crossref","first-page":"6302","DOI":"10.3390\/ijms24076302","article-title":"Gender\u2010Specific Impact of Sex Hormones on the Immune System","volume":"24","author":"Sciarra F.","year":"2023","journal-title":"International Journal of Molecular Sciences"},{"issue":"5","key":"e_1_2_9_34_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1001\/jama.2022.24140","article-title":"Management of Menopausal Symptoms: A Review","volume":"329","author":"Crandall C. J.","year":"2023","journal-title":"JAMA"},{"key":"e_1_2_9_35_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.archger.2024.105376","article-title":"Changes in Immune Cell Subtypes During Ageing","volume":"122","author":"Thin K. A.","year":"2024","journal-title":"Archives of Gerontology and Geriatrics"},{"key":"e_1_2_9_36_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.604591","article-title":"Immunosenescence Study of T Cells: A Systematic Review","volume":"11","author":"Rodriguez I. J.","journal-title":"Front Immunol 2020"},{"issue":"1","key":"e_1_2_9_37_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1210\/endrev\/bnac017","article-title":"Estrogen Receptor Signaling in the Immune System","volume":"44","author":"Chakraborty B.","year":"2023","journal-title":"Endocrine Reviews"},{"issue":"1","key":"e_1_2_9_38_1","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001932","article-title":"Estrogen Receptor Beta Signaling in CD8(+) T Cells Boosts T Cell Receptor Activation and Antitumor Immunity Through a Phosphotyrosine Switch","volume":"9","author":"Yuan B.","year":"2021","journal-title":"Journal for Immunotherapy of Cancer"},{"issue":"3","key":"e_1_2_9_39_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0060186","article-title":"Re\u2010Evaluation of PD\u20101 Expression by T Cells as a Marker for Immune Exhaustion During Siv Infection","volume":"8","author":"Hong J. J.","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"e_1_2_9_40_1","doi-asserted-by":"crossref","DOI":"10.1080\/22221751.2023.2208679","article-title":"The Unreversible Reduced but Persistent Activated Nk and CD8(+) T Cells in Severe\/Critical COVID\u201019 During Omicron Pandemic in China","volume":"12","author":"Qin L.","year":"2023","journal-title":"Emerging Microbes & Infections"},{"issue":"6","key":"e_1_2_9_41_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/ol.2025.15321","article-title":"Preoperative PD\u20101(+)CD4(+) Lymphocytes Reflect Immunological and Physical Frailty and Are Associated With Postoperative Infectious Complications Following Gastrectomy for Gastric Cancer","volume":"30","author":"Uehata N.","year":"2025","journal-title":"Oncology Letters"}],"container-title":["Immunity, Inflammation and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/iid3.70558","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/iid3.70558","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/iid3.70558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:44:57Z","timestamp":1792064697000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/iid3.70558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/iid3.70558"],"URL":"https:\/\/doi.org\/10.1002\/iid3.70558","archive":["Portico"],"relation":{},"ISSN":["2050-4527","2050-4527"],"issn-type":[{"value":"2050-4527","type":"print"},{"value":"2050-4527","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70558"}}