{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:22:43Z","timestamp":1771928563930,"version":"3.50.1"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003443","name":"Ministry of Education and Science of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2025-347"],"award-info":[{"award-number":["075-15-2025-347"]}],"id":[{"id":"10.13039\/501100003443","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-71-10051"],"award-info":[{"award-number":["23-71-10051"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To develop a mechanistic physiologically-based model describing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-lymphocyte homeostasis across the human lifespan, incorporating maturation, differentiation, migration aspects and the impact of age on distinct cell subpopulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A stepwise modeling approach was implemented by integrating published quantitative data on CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell concentration in blood and various tissues for narrowly defined age ranges, together with experimental kinetic parameters. The homeostatic CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-lymphocyte kinetics model was represented as a system of ordinary differential equations for four thymocyte subpopulations and six CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-lymphocyte subpopulations, incorporating five physiological compartments: the thymus, blood, lymphoid tissue, the gastro-intestinal tract, and lung tissue. A series of empirical functions was sequentially tested to describe age-related changes in homeostasis. Reciprocal cellular feedback functions were assessed for incorporation in the model, as an alternative to age-dependent functions. An extensive set of model evaluations was performed, including model validation on total and memory CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell concentrations, simulations of homeostasis perturbations following thymectomy, and global sensitivity analysis, to determine the processes most influential in shaping CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell homeostasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Age-related shifts in proliferation of na\u00efve and activated cells, differentiation of memory subsets, survival of recent thymic emigrants (RTE) and migration aspects of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells \u2013 together with reduced thymic output \u2013 were identified as key determinants of immune homeostasis. Sensitivity analyses showed that thymocyte and na\u00efve cell homeostasis drives early differentiation stages, whereas clonal expansion dominates memory and effector cell maintenance, with the influence of all processes declining with age. Although increased na\u00efve T-cell proliferation and reduced RTE death may partially compensate for thymic loss, these mechanisms are insufficient to restore long-term CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell counts after thymectomy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      By unifying diverse clinical and experimental observations within a multiscale mechanistic quantitative framework, the proposed model offers a robust tool for predicting CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell dynamics and assessing the impact of physiological changes or interventions on immune homeostasis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1742817","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T14:05:03Z","timestamp":1770213903000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiscale physiologically-based model of age-dependent CD4+ T-lymphocyte homeostasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Victoria","family":"Kulesh","sequence":"first","affiliation":[{"name":"Research Center of Model-Informed Drug Development, Sechenov First Moscow State Medical University","place":["Moscow, Russia"]},{"name":"Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences (INM RAS)","place":["Moscow, Russia"]},{"name":"Lomonosov Moscow State University","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirill","family":"Peskov","sequence":"additional","affiliation":[{"name":"Research Center of Model-Informed Drug Development, Sechenov First Moscow State Medical University","place":["Moscow, Russia"]},{"name":"Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences (INM RAS)","place":["Moscow, Russia"]},{"name":"Modeling & Simulation Decisions FZ-LLC","place":["Dubai, United Arab Emirates"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Helmlinger","sequence":"additional","affiliation":[{"name":"Quantitative Medicines Consulting","place":["Boston, MA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gennady","family":"Bocharov","sequence":"additional","affiliation":[{"name":"Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences (INM RAS)","place":["Moscow, Russia"]},{"name":"Institute for Computer Science and Mathematical Modelling, Sechenov First Moscow State Medical University","place":["Moscow, Russia"]},{"name":"Moscow Center of Fundamental and Applied Mathematics at INM RAS","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3152","article-title":"Expanding roles for CD4+ T cells in immunity to viruses","volume":"12","author":"Swain","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"663","DOI":"10.3390\/cancers15030663","article-title":"CAR-T: what is next","volume":"15","author":"Chen","year":"2023","journal-title":"Cancers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.3390\/pharmaceutics14061243","article-title":"Bispecific antibodies in cancer immunotherapy: A novel response to an old question","volume":"14","author":"Ord\u00f3\u00f1ez-Reyes","year":"2022","journal-title":"Pharmaceutics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41392-023-01471-y","article-title":"T cells in health and disease","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transduction Targeted Ther"},{"key":"B5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/j.1600-065X.2007.00497.x","article-title":"Quantification of T-cell dynamics: from telomeres to DNA labeling","volume":"216","author":"Borghans","year":"2007","journal-title":"Immunol Rev"},{"key":"B6","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1146\/annurev-immunol-032712-100010","article-title":"The biology of recent thymic emigrants","volume":"31","author":"Fink","year":"2013","journal-title":"Annu Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2013.09.003","article-title":"Lineage relationship of effector and memory T cells","volume":"25","author":"Restifo","year":"2013","journal-title":"Curr Opin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343751","article-title":"The who\u2019s who of T-cell differentiation: Human memory T-cell subsets","volume":"43","author":"Mahnke","year":"2013","journal-title":"Eur J Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nri2496","article-title":"Migration, maintenance and recall of memory T cells in peripheral tissues","volume":"9","author":"Woodland","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64096","article-title":"Causes, consequences, and reversal of immune system aging","volume":"123","author":"Montecino-Rodriguez","year":"2013","journal-title":"J Clin Invest"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-101721-040924","article-title":"Modeling T cell fate","volume":"41","author":"De Boer","year":"2023","journal-title":"Annu Rev Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.coisb.2019.10.002","article-title":"Current estimates of T cell kinetics in humans","volume":"18","author":"Macallan","year":"2019","journal-title":"Curr Opin Syst Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1059481","article-title":"Are homeostatic mechanisms aiding the reconstitution of the T-cell pool during lymphopenia in humans","volume":"13","author":"Baliu-Piqu\u00e9","year":"2022","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1250916","article-title":"Heterogeneity of memory T cells in aging","volume":"14","author":"Jain","year":"2023","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.23013.028","article-title":"Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels","volume":"6","author":"Gossel","year":"2017","journal-title":"eLife"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780132207","article-title":"Age-related reference ranges: Significance tests for models and confidence intervals for centiles","volume":"13","author":"Wade","year":"1994","journal-title":"Stat Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200520","article-title":"Age-dependent normalization functions for T lymphocytes in healthy individuals","volume":"210","author":"Schr\u00f6ter","year":"2023","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1475871","article-title":"Systematic review and quantitative meta-analysis of age-dependent human T-lymphocyte homeostasis","volume":"16","author":"Kulesh","year":"2025","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(41)80232-7","article-title":"The blood volume in normal infants and children","volume":"18","author":"Brines","year":"1941","journal-title":"J Pediatrics"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gls220","article-title":"The effect of age-related differences in body size and composition on cardiovascular determinants of VO2max","volume":"68","author":"Carrick-Ranson","year":"2013","journal-title":"Journals Gerontology: Ser A"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(60)80287-9","article-title":"The blood volume of infants: III. Alterations in the first hours after birth","volume":"56","author":"Sisson","year":"1960","journal-title":"J Pediatrics"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1994.76.5.2059","article-title":"Total blood volume in healthy young and older men","volume":"76","author":"Davy","year":"1994","journal-title":"J Appl Physiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00706.2023","article-title":"The effect of chronic habitual exercise on oxygen carrying capacity and blood compartment volumes in older adults","volume":"136","author":"Wakeham","year":"2024","journal-title":"J Appl Physiol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics2040364","article-title":"Drug development for pediatric populations: regulatory aspects","volume":"2","author":"Zisowsky","year":"2010","journal-title":"Pharmaceutics"},{"key":"B25","article-title":"The weight of the human thymus gland at necropsy","volume":"131","author":"Kendall","year":"1980","journal-title":"J Anat"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1001\/archpedi.1932.01950050114011","article-title":"The weight of the thymus gland in health and in disease","volume":"43","author":"Boyd","year":"1932","journal-title":"Am J Dis Children"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1321309","article-title":"An integrative mechanistic model of thymocyte dynamics","volume":"15","author":"Kulesh","year":"2024","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-341396","article-title":"Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration","volume":"118","author":"van Gent","year":"2011","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00020","article-title":"IL-7-induced proliferation of human naive CD4 T-cells relies on continued thymic activity","volume":"8","author":"Silva","year":"2017","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00933\/full","article-title":"Dynamics of recent thymic emigrants in young adult mice","volume":"8","author":"van Hoeven","year":"2017","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080996","article-title":"Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function","volume":"206","author":"Haines","year":"2009","journal-title":"J Exp Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709713105","article-title":"Sparse production but preferential incorporation of recently produced na\u00efve T cells in the human peripheral pool","volume":"105","author":"Vrisekoop","year":"2008","journal-title":"Proc Natl Acad Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9478","article-title":"Normal physiology and HIV pathophysiology of human T-cell dynamics","volume":"105","author":"Richman","year":"2000","journal-title":"J Clin Invest"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/360264a0","article-title":"Lifespan of human lymphocyte subsets defined by CD45 isoforms","volume":"360","author":"Michie","year":"1992","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200323763","article-title":"Measurement and modeling of human T cell kinetics","volume":"33","author":"Macallan","year":"2003","journal-title":"Eur J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040341","article-title":"Rapid turnover of effector\u2013memory CD4+ T cells in healthy humans","volume":"200","author":"Macallan","year":"2004","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.3.1787","article-title":"Direct measurement of T cell subset kinetics in vivo in elderly men and women1","volume":"173","author":"Wallace","year":"2004","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.3390\/cancers13112782","article-title":"Early survival prediction framework in CD19-specific CAR-T cell immunotherapy using a quantitative systems pharmacology model","volume":"13","author":"Mueller-Schoell","year":"2021","journal-title":"Cancers"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2000.01098.x","article-title":"Spontaneous and oxidative stress-induced programmed cell death in lymphocytes from patients with ataxia telangiectasia (AT)","volume":"119","author":"Schubert","year":"2000","journal-title":"Clin Exp Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.9.3707","article-title":"In vivo estimates of division and death rates of human T lymphocytes","volume":"92","author":"Mclean","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nri778","article-title":"Effector and memory T-cell differentiation: implications for vaccine development","volume":"2","author":"Kaech","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1097\/00042560-200205010-00006","article-title":"Dynamics of naive and memory CD4+ T lymphocytes in HIV-1 disease progression","volume":"30","author":"Bajaria","year":"2002","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B43","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/0008-8749(73)90180-9","article-title":"Circulating T and B lymphocytes of the mouse: I. Migratory properties","volume":"7","author":"Sprent","year":"1973","journal-title":"Cell Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/0008-8749(73)90181-0","article-title":"Circulating T and B lymphocytes of the mouse: II","volume":"7","author":"Sprent","year":"1973","journal-title":"Lifespan. Cell Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211717109","article-title":"Quantification of lymph node transit times reveals differences in antigen surveillance strategies of na\u00efve CD4+ and CD8+ T cells","volume":"109","author":"Mandl","year":"2012","journal-title":"Proc Natl Acad Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242358099","article-title":"In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted","volume":"99","author":"Ribeiro","year":"2002","journal-title":"Proc Natl Acad Sci"},{"key":"B47","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1182\/blood-2007-05-088435","article-title":"HIV-1\u2013induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo","volume":"111","author":"Biancotto","year":"2008","journal-title":"Blood"},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-030-57204-4_10","article-title":"Experimental and mathematical approaches to quantify recirculation kinetics of lymphocytes","volume-title":"Mathematical, Computational and Experimental T Cell Immunology","author":"Ganusov","year":"2021"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(76)90058-7","article-title":"Fate of H2-activated T lymphocytes in syngeneic hosts: II. Residence in recirculating lymphocyte pool and capacity to migrate to allografts","volume":"21","author":"Sprent","year":"1976","journal-title":"Cell Immunol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jtbi.2008.11.007","article-title":"Scaling aspects of lymphocyte trafficking","volume":"257","author":"Perelson","year":"2009","journal-title":"J Theor Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1235","article-title":"Comparative biology of mouse versus human cells: modelling human cancer in mice","volume":"3","author":"Rangarajan","year":"2003","journal-title":"Nat Rev Cancer"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2446","article-title":"A human memory T cell subset with stem cell\u2013like properties","volume":"17","author":"Gattinoni","year":"2011","journal-title":"Nat Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.02.010","article-title":"Toward a general model of CD4+ T cell subset specification and memory cell formation","volume":"56","author":"Osum","year":"2023","journal-title":"Immunity"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9592.2011.03534.x","article-title":"Predicting weight using postmenstrual age \u2013 neonates to adults","volume":"21","author":"Sumpter","year":"2011","journal-title":"Pediatr Anesthesia"},{"key":"B55","first-page":"1","volume-title":"A framework for quantitative systems pharmacology model execution","author":"Sokolov","year":"2025"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12669","article-title":"Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility","volume":"10","author":"Musuamba","year":"2021","journal-title":"CPT: Pharmacometrics Syst Pharmacol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13208","article-title":"Landscape of regulatory quantitative systems pharmacology submissions to the U.S. Food and Drug Administration: An update report","volume":"13","author":"Bai","year":"2024","journal-title":"CPT: Pharmacometrics Syst Pharmacol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12381","article-title":"Best practices to maximize the use and reuse of quantitative and systems pharmacology models: recommendations from the United Kingdom quantitative and systems pharmacology network","volume":"8","author":"Cucurull-Sanchez","year":"2019","journal-title":"CPT: Pharmacometrics Syst Pharmacol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12755","article-title":"Evaluation framework for systems models","volume":"11","author":"Braakman","year":"2022","journal-title":"CPT: Pharmacometrics Syst Pharmacol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2308511120","article-title":"The total mass, number, and distribution of immune cells in the human body","volume":"120","author":"Sender","year":"2023","journal-title":"Proc Natl Acad Sci"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2008.04.011","article-title":"A methodology for performing global uncertainty and sensitivity analysis in systems biology","volume":"254","author":"Marino","year":"2008","journal-title":"J Theor Biol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/S1471-4906(02)02337-2","article-title":"Lymphocyte kinetics: the interpretation of labelling data","volume":"23","author":"Asquith","year":"2002","journal-title":"Trends Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00474","article-title":"Physiologically based simulations of deuterated glucose for quantifying cell turnover in humans","volume":"8","author":"Lahoz-Beneytez","year":"2017","journal-title":"Front Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00573","article-title":"The rules of human T cell fate in vivo","volume":"11","author":"Costa del Amo","year":"2020","journal-title":"Front Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0180-1","article-title":"Mechanisms underlying T cell ageing","volume":"19","author":"Goronzy","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15770","article-title":"Hallmarks of the aging T-cell system","volume":"288","author":"Zhang","year":"2021","journal-title":"FEBS J"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12311","article-title":"Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover","volume":"14","author":"Westera","year":"2015","journal-title":"Aging Cell"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2008.01052.x","article-title":"Age-matched lymphocyte subpopulation reference values in childhood and adolescence: application of exponential regression analysis","volume":"80","author":"Huenecke","year":"2008","journal-title":"Eur J Haematology"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.1985.tb01916.x","article-title":"The involution of the ageing human thymic epithelium is independent of puberty","volume":"22","author":"Steinmann","year":"1985","journal-title":"Scandinavian J Immunol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"101839","DOI":"10.1016\/j.smim.2023.101839","article-title":"Better safe than sorry: Naive T-cell dynamics in healthy ageing","volume":"70","author":"de Boer","year":"2023","journal-title":"Semin Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201235","article-title":"Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults","volume":"189","author":"Sauce","year":"2012","journal-title":"J Immunol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.774780","article-title":"Early thymectomy is associated with long-term impairment of the immune system: A systematic review","volume":"12","author":"Cavalcanti","year":"2021","journal-title":"Front Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201746971","article-title":"Human neonatal thymectomy induces altered B-cell responses and autoreactivity","volume":"47","author":"van den Broek","year":"2017","journal-title":"Eur J Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13671","article-title":"Age-related thymic involution: Mechanisms and functional impact","volume":"21","author":"Liang","year":"2022","journal-title":"Aging Cell"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.975858","article-title":"Effects of sex steroids on thymic epithelium and thymocyte development","volume":"13","author":"Taves","year":"2022","journal-title":"Front Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2005523v","article-title":"Human TSCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness","volume":"16","author":"Costa del Amo","year":"2018","journal-title":"PLoS Biol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3003179","article-title":"Two distinct subpopulations of human stem-like memory T cells exhibit complementary roles in self-renewal and clonal longevity","volume":"23","author":"Koftori","year":"2025","journal-title":"PLoS Biol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aas9673","article-title":"Location, location, location: Tissue resident memory T cells in mice and humans","volume":"4","author":"Szabo","year":"2019","journal-title":"Sci Immunol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.09.020","article-title":"Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets","volume":"38","author":"Sathaliyawala","year":"2013","journal-title":"Immunity"},{"key":"B80","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/s41467-020-14396-9","article-title":"Sexual-dimorphism in human immune system aging","volume":"11","author":"M\u00e1rquez","year":"2020","journal-title":"Nat Commun"},{"key":"B81","doi-asserted-by":"publisher","first-page":"101323","DOI":"10.1016\/j.arr.2021.101323","article-title":"Ageing of the gut microbiome: Potential influences on immune senescence and inflammageing","volume":"68","author":"Conway","year":"2021","journal-title":"Ageing Res Rev"},{"key":"B82","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s10928-011-9232-2","article-title":"Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human","volume":"39","author":"Shah","year":"2012","journal-title":"J Pharmacokinet Pharmacodynamics"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113148","article-title":"Aging-related cellular, structural and functional changes in the lymph nodes: A significant component of immunosenescence","volume":"10","author":"Cakala-Jakimowicz","year":"2021","journal-title":"Overview. Cells"},{"key":"B84","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12979-024-00433-4","article-title":"The effect of T cell aging on the change of human tissue structure","volume":"21","author":"Xu","year":"2024","journal-title":"Immun Ageing"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02125","article-title":"Antigen-specific CD4+ T cells exhibit distinct kinetic and phenotypic patterns during primary and secondary responses to infection","volume":"11","author":"Malhotra","year":"2020","journal-title":"Front Immunol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"RP104278","DOI":"10.7554\/eLife.104278.3","article-title":"Tissue-resident memory CD4+ T cells are sustained by site-specific levels of self-renewal and continuous replacement","volume":"14","author":"Chandler","year":"2025","journal-title":"eLife"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1742817\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:31:27Z","timestamp":1771925487000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1742817\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":86,"alternative-id":["10.3389\/fimmu.2026.1742817"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1742817","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,4]]},"article-number":"1742817"}}