{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:30:36Z","timestamp":1791898236651,"version":"4.3.4"},"reference-count":133,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI121147"],"award-info":[{"award-number":["R01AI121147"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 AG020494"],"award-info":[{"award-number":["T32 AG020494"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and\/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution\/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.<\/jats:p>","DOI":"10.3390\/cells10030628","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T11:56:55Z","timestamp":1615550215000},"page":"628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5317-9863","authenticated-orcid":false,"given":"Weikan","family":"Wang","sequence":"first","affiliation":[{"name":"Cell Biology, Immunology, and Microbiology Graduate Program, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0603-7088","authenticated-orcid":false,"given":"Rachel","family":"Thomas","sequence":"additional","affiliation":[{"name":"Cell Biology, Immunology, and Microbiology Graduate Program, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyoung","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3326-4753","authenticated-orcid":false,"given":"Dong-Ming","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology &amp; Genetics, University of North Texas Health Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4049\/jimmunol.2000380","article-title":"Role of Aging and the Immune Response to Respiratory Viral Infections: Potential Implications for COVID-19","volume":"205","author":"Chen","year":"2020","journal-title":"J. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"O\u2019Driscoll, M., Dos Santos, G.R., Wang, L., Cummings, D.A.T., Azman, A.S., Paireau, J., Fontanet, A., Cauchemez, S., and Salje, H. (2020). Age-specific mortality and immunity patterns of SARS-CoV-2. Nature, 590.","DOI":"10.1101\/2020.08.24.20180851"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.abb0762","article-title":"Aging immunity may exacerbate COVID-19","volume":"369","author":"Akbar","year":"2020","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.immuni.2020.04.023","article-title":"Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals","volume":"52","author":"Ni","year":"2020","journal-title":"Immunity"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41577-020-00436-4","article-title":"Not just antibodies: B cells and T cells mediate immunity to COVID-19","volume":"20","author":"Cox","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41577-020-0402-6","article-title":"T cell responses in patients with COVID-19","volume":"20","author":"Chen","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/s41590-020-0798-y","article-title":"T cells in COVID-19\u2014United in diversity","volume":"21","author":"Swadling","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1038\/s41590-020-0782-6","article-title":"Broad and strong memory CD4(+) and CD8(+) T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19","volume":"21","author":"Peng","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yu, J., Tostanoski, L.H., Peter, L., Mercado, N.B., McMahan, K., Mahrokhian, S.H., Nkolola, J.P., Liu, P., Li, Z., and Chandrashekar, A. (2020). DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science.","DOI":"10.1126\/science.abc6284"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sadeghi, A., Tahmasebi, S., Mahmood, A., Kuznetsova, M., Valizadeh, H., Taghizadieh, A., Nazemiyeh, M., Aghebati-Maleki, L., Jadidi-Niaragh, F., and Abbaspour-Aghdam, S. (2020). Th17 and Treg cells function in SARS-CoV2 patients compared with healthy controls. J. Cell. Physiol.","DOI":"10.1002\/jcp.30047"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1016\/j.cell.2020.10.001","article-title":"Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4(+) T Cells in COVID-19","volume":"183","author":"Meckiff","year":"2020","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"596553","DOI":"10.3389\/fimmu.2020.596553","article-title":"\u00c1ngel Negative Clinical Evolution in COVID-19 Patients Is Frequently Accompanied with an Increased Proportion of Undifferentiated Th Cells and a Strong Underrepresentation of the Th1 Subset","volume":"11","author":"Garrido","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.humimm.2020.08.006","article-title":"Characteristics of immune cells and cytokines in patients with coronavirus disease 2019 in Guangzhou, China","volume":"81","author":"Chen","year":"2020","journal-title":"Hum. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2002182","DOI":"10.1183\/13993003.02182-2020","article-title":"Potential of regulatory T-cell-based therapies in the management of severe COVID-19","volume":"56","author":"Das","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s00281-020-00821-0","article-title":"Shelter from the cytokine storm: Pitfalls and prospects in the development of SARS-CoV-2 vaccines for an elderly population","volume":"42","author":"Ciabattini","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12979-020-0173-8","article-title":"Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging","volume":"17","author":"Thomas","year":"2020","journal-title":"Immun. Ageing"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"579220","DOI":"10.3389\/fimmu.2020.579220","article-title":"I mmunosenescence and Inflammaging: Risk Factors of Severe COVID-19 in Older People","volume":"11","author":"Pietrobon","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"573662","DOI":"10.3389\/fimmu.2020.573662","article-title":"Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?","volume":"11","author":"Hazeldine","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1016\/j.sjbs.2020.05.024","article-title":"Current scenario of COVID-19 in pediatric age group and physiology of immune and thymus response","volume":"27","author":"Rehman","year":"2020","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_20","first-page":"1","article-title":"Potential impact of SARS-CoV-2 infection on the thymus","volume":"67","author":"Lins","year":"2020","journal-title":"Can. J. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1093\/cid\/ciaa630","article-title":"Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells","volume":"71","author":"Liu","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","first-page":"465","article-title":"Virological assessment of hospitalized patients with COVID-2019","volume":"581","author":"Corman","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.jfma.2020.02.009","article-title":"SARS-CoV-2 infection in children: Transmission dynamics and clinical characteristics","volume":"119","author":"Cao","year":"2020","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105924","DOI":"10.1016\/j.ijantimicag.2020.105924","article-title":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges","volume":"55","author":"Lai","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zamai, L. (2020). The Yin and Yang of ACE\/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients. Cells, 9.","DOI":"10.3390\/cells9071704"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"573","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":"ref_27","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","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.it.2016.09.002","article-title":"Senescence of T Lymphocytes: Implications for Enhancing Human Immunity","volume":"37","author":"Akbar","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1073\/pnas.1714478115","article-title":"Thymic involution and rising disease incidence with age","volume":"115","author":"Palmer","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"606","DOI":"10.18632\/aging.100487","article-title":"Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus","volume":"4","author":"Sun","year":"2012","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eabe8063","DOI":"10.1126\/sciimmunol.abe8063","article-title":"The known unknowns of T cell immunity to COVID-19","volume":"5","author":"Karlsson","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41392-020-0148-4","article-title":"Lymphopenia predicts disease severity of COVID-19: A descriptive and predictive study","volume":"5","author":"Tan","year":"2020","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41586-020-2550-z","article-title":"SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls","volume":"584","author":"Tan","year":"2020","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/j.cell.2020.05.015","article-title":"Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals","volume":"181","author":"Grifoni","year":"2020","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Weiskopf, D., Schmitz, K.S., Raadsen, M.P., Grifoni, A., Okba, N.M.A., Endeman, H., van den Akker, J.P.C., Molenkamp, R., Koopmans, M.P.G., and van Gorp, E.C.M. (2020). Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci. Immunol., 5.","DOI":"10.1126\/sciimmunol.abd2071"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2598-9","article-title":"SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19","volume":"587","author":"Braun","year":"2020","journal-title":"Nature"},{"key":"ref_37","first-page":"1","article-title":"Molecular immune pathogenesis and diagnosis of COVID-19","volume":"19","author":"Li","year":"2020","journal-title":"J. Pharm. Anal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1111\/all.14429","article-title":"Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors","volume":"75","author":"Radzikowska","year":"2020","journal-title":"Allergy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41577-020-00470-2","article-title":"Leukocyte trafficking to the lungs and beyond: Lessons from influenza for COVID-19","volume":"21","author":"Alon","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1056\/NEJM199501193320303","article-title":"Age, Thymopoiesis, and CD4+ T-Lymphocyte Regeneration after Intensive Chemotherapy","volume":"332","author":"Mackall","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/j.1365-2249.2010.04209.x","article-title":"Tracing thymic output in older individuals","volume":"161","author":"Mitchell","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12685","DOI":"10.1128\/JVI.01131-07","article-title":"Efficient Thymopoiesis Contributes to the Maintenance of Peripheral CD4 T Cells during Chronic Human Immunodeficiency Virus Type 2 Infection","volume":"81","author":"Gautier","year":"2007","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1084\/jem.20050341","article-title":"T cell aging: Naive but not young","volume":"201","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1111\/j.1365-2567.2010.03255.x","article-title":"T-cell exhaustion: Characteristics, causes and conversion","volume":"129","author":"Yi","year":"2010","journal-title":"Immunology"},{"key":"ref_45","first-page":"280","article-title":"Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma","volume":"3","author":"Gui","year":"2012","journal-title":"Aging Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1093\/intimm\/dxm095","article-title":"The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells","volume":"19","author":"Gui","year":"2007","journal-title":"Int. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s11357-013-9564-5","article-title":"Thymus and aging: Morphological, radiological, and functional overview","volume":"36","author":"Rezzani","year":"2014","journal-title":"Age"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.exger.2017.10.024","article-title":"Age and immunity: What is \u201cimmunosenescence\u201d?","volume":"105","author":"Pawelec","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5825","DOI":"10.4049\/jimmunol.1500082","article-title":"Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation","volume":"194","author":"Coder","year":"2015","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.molmed.2010.03.003","article-title":"Inflammatory networks during cellular senescence: Causes and consequences","volume":"16","author":"Freund","year":"2010","journal-title":"Trends Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1016\/j.febslet.2005.02.055","article-title":"Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity","volume":"579","author":"Franceschi","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.smim.2018.10.008","article-title":"Inflammaging 2018: An update and a model","volume":"40","author":"Franceschi","year":"2018","journal-title":"Semin. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3389\/fimmu.2017.01960","article-title":"Immunosenescence and Inflamm-Aging as Two Sides of the Same Coin: Friends or Foes?","volume":"8","author":"Fulop","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Oh, J., Wang, W., Thomas, R., and Su, D.-M. (2017). Capacity of tTreg generation is not impaired in the atrophied thymus. PLoS Biol., 15.","DOI":"10.1371\/journal.pbio.2003352"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.coi.2012.04.005","article-title":"Homeostasis and function of regulatory T cells in aging","volume":"24","author":"Raynor","year":"2012","journal-title":"Curr. Opin. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"18333","DOI":"10.1073\/pnas.0910139106","article-title":"Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects","volume":"106","author":"Tsukamoto","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.4049\/jimmunol.1001668","article-title":"Bim Dictates Naive CD4 T Cell Lifespan and the Development of Age-Associated Functional Defects","volume":"185","author":"Tsukamoto","year":"2010","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"156","DOI":"10.4049\/jimmunol.1001505","article-title":"A Major Role for Bim in Regulatory T Cell Homeostasis","volume":"186","author":"Chougnet","year":"2010","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/ni1033","article-title":"Age-related changes in lymphocyte development and function","volume":"5","author":"Linton","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.0105-2896.2005.00256.x","article-title":"CD28 extinction in human T cells: Altered functions and the program of T-cell senescence","volume":"205","author":"Vallejo","year":"2005","journal-title":"Immunol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"110887","DOI":"10.1016\/j.exger.2020.110887","article-title":"T cells, aging and senescence","volume":"134","author":"Pangrazzi","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4049\/jimmunol.1602005","article-title":"Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+ T Cells","volume":"199","author":"Sato","year":"2017","journal-title":"J. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.3389\/fimmu.2019.02247","article-title":"Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention","volume":"10","author":"Aiello","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1474-9726.2009.00489.x","article-title":"Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging","volume":"8","author":"Liu","year":"2009","journal-title":"Aging Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1182\/blood-2010-09-304402","article-title":"Expression of p16INK4a prevents cancer and promotes aging in lymphocytes","volume":"117","author":"Liu","year":"2011","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.exger.2005.11.003","article-title":"Age-related changes in cell surface and senescence markers in the spleen of DBA\/2 mice: A flow cytometric analysis","volume":"41","author":"Connoy","year":"2006","journal-title":"Exp. Gerontol."},{"key":"ref_67","first-page":"248","article-title":"Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection","volume":"3","author":"Xia","year":"2012","journal-title":"Aging Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression","volume":"5","author":"Desprez","year":"2010","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.smim.2018.09.003","article-title":"The integration of inflammaging in age-related diseases","volume":"40","author":"Fulop","year":"2018","journal-title":"Semin. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.mad.2006.04.003","article-title":"The immune risk phenotype is associated with IL-6 in the terminal decline stage: Findings from the Swedish NONA immune longitudinal study of very late life functioning","volume":"127","author":"Wikby","year":"2006","journal-title":"Mech. Ageing Dev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.4049\/jimmunol.167.6.3231","article-title":"Down-Regulation of CD28 Expression by TNF-\u03b1","volume":"167","author":"Bryl","year":"2001","journal-title":"J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1002\/art.21353","article-title":"Modulation of CD28 expression with anti-tumor necrosis factor \u03b1 therapy in rheumatoid arthritis","volume":"52","author":"Bryl","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"18778","DOI":"10.18632\/aging.103989","article-title":"SARS-CoV-2, immunosenescence and inflammaging: Partners in the COVID-19 crime","volume":"12","author":"Domingues","year":"2020","journal-title":"Aging"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.3389\/fimmu.2020.01748","article-title":"Remodeling of the Immune Response with Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response","volume":"11","author":"Cunha","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s12603-020-1416-2","article-title":"COVID-19, Virology and Geroscience: A Perspective","volume":"24","author":"Vellas","year":"2020","journal-title":"J. Nutr. Health Aging"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Kellogg, C., and Equils, O. (2020). The role of the thymus in COVID-19 disease severity: Implications for antibody treatment and immunization. Hum. Vaccines Immunother., 1\u20136.","DOI":"10.1080\/21645515.2020.1818519"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fimmu.2012.00051","article-title":"Molecular mechanisms of treg-mediated T cell suppression","volume":"3","author":"Schmidt","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.3389\/fimmu.2019.03100","article-title":"Treg Heterogeneity, Function, and Homeostasis","volume":"10","author":"Shevyrev","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/acel.12191","article-title":"Aging is associated with increased regulatory T-cell function","volume":"13","author":"Garg","year":"2014","journal-title":"Aging Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.4049\/jimmunol.181.3.1835","article-title":"Functional Regulatory T Cells Accumulate in Aged Hosts and Promote Chronic Infectious Disease Reactivation","volume":"181","author":"Lages","year":"2008","journal-title":"J. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nri2189","article-title":"Regulatory T cells and infection: A dangerous necessity","volume":"7","author":"Belkaid","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1158\/2326-6066.CIR-18-0066","article-title":"Treg Fragility: A Prerequisite for Effective Antitumor Immunity?","volume":"6","author":"Vignali","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Frimpong-Boateng, K., Van Rooijen, N., and Geiben-Lynn, R. (2010). Regulatory T Cells Suppress Natural Killer Cells during Plasmid DNA Vaccination in Mice, Blunting the CD8+ T Cell Immune Response by the Cytokine TGF\u03b2. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012281"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5150","DOI":"10.4049\/jimmunol.1001114","article-title":"A Peptide Inhibitor of FOXP3 Impairs Regulatory T Cell Activity and Improves Vaccine Efficacy in Mice","volume":"185","author":"Casares","year":"2010","journal-title":"J. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Pierce, C.A., Preston-Hurlburt, P., Dai, Y., Aschner, C.B., Cheshenko, N., Galen, B., Garforth, S.J., Herrera, N.G., Jangra, R.K., and Morano, N.C. (2020). Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Sci. Transl. Med., 12.","DOI":"10.1126\/scitranslmed.abd5487"},{"key":"ref_86","first-page":"1","article-title":"Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia","volume":"11","author":"Meschiari","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The trinity of COVID-19: Immunity, inflammation and intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40560-020-00453-4","article-title":"Lymphopenia in severe coronavirus disease-2019 (COVID-19): Systematic review and meta-analysis","volume":"8","author":"Huang","year":"2020","journal-title":"J. Intensive Care"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1111\/apa.15270","article-title":"Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults","volume":"109","author":"Ludvigsson","year":"2020","journal-title":"Acta Paediatr."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1073\/pnas.81.9.2882","article-title":"Thymosin increases production of T-cell growth factor by normal human peripheral blood lymphocytes","volume":"81","author":"Zatz","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1080\/14712598.2018.1484447","article-title":"From thymus to cystic fibrosis: The amazing life of thymosin alpha 1","volume":"18","author":"Garaci","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1196\/annals.1415.039","article-title":"Thymosin 1: A Historical Overview","volume":"1112","author":"Garaci","year":"2007","journal-title":"Ann. N. Y. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3109\/08830185.2013.870171","article-title":"FOXN1 in Organ Development and Human Diseases","volume":"33","author":"Palamaro","year":"2014","journal-title":"Int. Rev. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"16613","DOI":"10.1073\/pnas.1004623107","article-title":"Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage","volume":"107","author":"Corbeaux","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.1074\/jbc.M109.072124","article-title":"Postnatal Tissue-specific Disruption of Transcription Factor FoxN1 Triggers Acute Thymic Atrophy","volume":"285","author":"Cheng","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1182\/blood-2008-05-156265","article-title":"Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner","volume":"113","author":"Chen","year":"2009","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Oh, J., Wang, W., Thomas, R., and Su, D.-M. (2020). Thymic rejuvenation via FOXN1-reprogrammed embryonic fibroblasts (FREFs) to counteract age-related inflammation. JCI Insight, 5.","DOI":"10.1172\/jci.insight.140313"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1016\/j.jaci.2017.03.020","article-title":"Thymus transplantation for complete DiGeorge syndrome: European experience","volume":"140","author":"Davies","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.clim.2010.02.007","article-title":"Thymus transplantation","volume":"135","author":"Markert","year":"2010","journal-title":"Clin. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.4049\/jimmunol.175.6.4112","article-title":"An IL-7 Fusion Protein That Shows Increased Thymopoietic Ability","volume":"175","author":"Henson","year":"2005","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.coi.2013.06.002","article-title":"Thymic rejuvenation and aging","volume":"25","author":"Ventevogel","year":"2013","journal-title":"Curr. Opin. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1182\/blood.V97.5.1491","article-title":"IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation","volume":"97","author":"Mackall","year":"2001","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nri2970","article-title":"Harnessing the biology of IL-7 for therapeutic application","volume":"11","author":"Mackall","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/s41590-019-0479-x","article-title":"Flip the coin: IL-7 and IL-7R in health and disease","volume":"20","author":"Barata","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/S0264-410X(99)00498-3","article-title":"Thymic atrophy in the mouse is a soluble problem of the thymic environment","volume":"18","author":"Aspinall","year":"2000","journal-title":"Vaccine"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.immuni.2008.11.002","article-title":"Homeostasis of Naive and Memory T Cells","volume":"29","author":"Surh","year":"2008","journal-title":"Immunity"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3389\/fimmu.2017.00451","article-title":"IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection","volume":"8","author":"Chiodi","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e2016485","DOI":"10.1001\/jamanetworkopen.2020.16485","article-title":"Association of Interleukin 7 Immunotherapy with Lymphocyte Counts Among Patients with Severe Coronavirus Disease 2019 (COVID-19)","volume":"3","author":"Laterre","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41423-020-0516-6","article-title":"Immune monitoring of interleukin-7 compassionate use in a critically ill COVID-19 patient","volume":"17","author":"Monneret","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"569633","DOI":"10.3389\/fendo.2020.569633","article-title":"A Suggested Role of Human Growth Hormone in Control of the COVID-19 Pandemic","volume":"11","author":"Elkarow","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1111\/j.1474-9726.2010.00611.x","article-title":"Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1\/ PD-L1 pathway","volume":"9","author":"Lages","year":"2010","journal-title":"Aging Cell"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Parmigiani, A., Alcaide, M.L., Freguja, R., Pallikkuth, S., Frasca, D., Fischl, M.A., and Pahwa, S. (2013). Impaired Antibody Response to Influenza Vaccine in HIV-Infected and Uninfected Aging Women Is Associated with Immune Activation and Inflammation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079816"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"583019","DOI":"10.3389\/fimmu.2020.583019","article-title":"Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly","volume":"11","author":"Pereira","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"12353","DOI":"10.1002\/jcp.28042","article-title":"mTOR Signaling pathway as a master regulator of memory CD8(+) T-cells, Th17, and NK cells development and their functional properties","volume":"234","author":"Rostamzadeh","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_115","first-page":"108","article-title":"mTOR regulates memory CD8 T-cell differentiation","volume":"460","author":"Araki","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"eaaq1564","DOI":"10.1126\/scitranslmed.aaq1564","article-title":"TORC1 inhibition enhances immune function and reduces infections in the elderly","volume":"10","author":"Mannick","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"450","DOI":"10.3389\/fimmu.2016.00450","article-title":"Immunosenescence-Related Transcriptomic and Immunologic Changes in Older Individuals Following Influenza Vaccination","volume":"7","author":"Kennedy","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.coi.2014.01.006","article-title":"Metabolism of activated T lymphocytes","volume":"27","author":"Maciolek","year":"2014","journal-title":"Curr. Opin. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.4049\/jimmunol.1701200","article-title":"Biotin Deficiency Induces Th1- and Th17-Mediated Proinflammatory Responses in Human CD4+ T Lymphocytes via Activation of the mTOR Signaling Pathway","volume":"200","author":"Elahi","year":"2018","journal-title":"J. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.4049\/jimmunol.1601689","article-title":"DDIT4 and Associated lncDDIT4 Modulate Th17 Differentiation through the DDIT4\/TSC\/mTOR Pathway","volume":"200","author":"Zhang","year":"2018","journal-title":"J. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41232-020-00146-3","article-title":"How COVID-19 induces cytokine storm with high mortality","volume":"40","author":"Hojyo","year":"2020","journal-title":"Inflamm. Regen."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"570993","DOI":"10.3389\/fimmu.2020.570993","article-title":"Controlling Cytokine Storm Is Vital in COVID-19","volume":"11","author":"Tang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1177\/1073858420941476","article-title":"COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation","volume":"26","author":"Kempuraj","year":"2020","journal-title":"Neuroscientist"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.4049\/jimmunol.0803449","article-title":"Modulation of T lymphocyte replicative senescence via TNF-\u03b1 inhibition: Role of caspase-3","volume":"182","author":"Parish","year":"2009","journal-title":"J. Immunol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1016\/j.vaccine.2013.05.003","article-title":"Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine","volume":"31","author":"Frasca","year":"2013","journal-title":"Vaccine"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.exger.2014.01.004","article-title":"High TNF-\u03b1 levels in resting B cells negatively correlate with their response","volume":"54","author":"Frasca","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1096\/fj.201701498RR","article-title":"Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat","volume":"33","author":"Khan","year":"2018","journal-title":"FASEB J."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.micinf.2017.08.013","article-title":"Blockage of regulatory T cells augments induction of protective immune responses by influenza virus-like particles in aged mice","volume":"19","author":"Wen","year":"2017","journal-title":"Microbes Infect."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/s12967-019-1967-3","article-title":"Blockade of TGF-beta signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells","volume":"17","author":"Polanczyk","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.7150\/ijbs.46891","article-title":"A potential treatment of COVID-19 with TGF-beta blockade","volume":"16","author":"Chen","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nri3622","article-title":"Regulation of immune responses by extracellular vesicles","volume":"14","author":"Robbins","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"5899","DOI":"10.1096\/fj.201800059R","article-title":"Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance","volume":"32","author":"Wang","year":"2018","journal-title":"FASEB J."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.cell.2020.08.017","article-title":"Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19","volume":"183","author":"Sekine","year":"2020","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/628\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:33Z","timestamp":1760160873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/628"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":133,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["cells10030628"],"URL":"https:\/\/doi.org\/10.3390\/cells10030628","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]}}}