{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:52:07Z","timestamp":1778626327330,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WI 5021-21 \u2013 FOR2799"],"award-info":[{"award-number":["WI 5021-21 \u2013 FOR2799"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009397","name":"Medizinischen Fakult\u00e4t, Eberhard Karls Universit\u00e4t T\u00fcbingen","doi-asserted-by":"publisher","award":["2509-0-0"],"award-info":[{"award-number":["2509-0-0"]}],"id":[{"id":"10.13039\/501100009397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FP7 259679"],"award-info":[{"award-number":["FP7 259679"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Adaptive as well as innate immune traits are variously affected by environmental and genetic influences, but little is known about the impact of genetics on the diversity, differentiation and functionality of \u03b3\u03b4 T cells in humans. Here, we analyzed a cohort of 95 middle-aged twins from the Danish Twin Registry. The differentiation status of peripheral \u03b1\u03b2 and \u03b3\u03b4 T cells was assessed by flow cytometry based on the surface expression of CD27, CD28 and CD45RA. Our data confirm the established associations of latent cytomegalovirus (CMV) infection with an accumulation of late differentiated memory T cells in the \u03b1\u03b2 compartment as well as in the V\u03b41+ \u03b3\u03b4 T cell subset. A comparison of differentiation phenotypes of \u03b3\u03b4 and \u03b1\u03b2 T cells that were not affected by CMV seropositivity identified a significant correlation of early differentiated (ED) V\u03b42+ and intermediate differentiated (ID) CD4+ T cells in monozygotic (MZ), but not in dizygotic (DZ) co-twins. Thus, our data suggest a genetic influence on the differentiation of \u03b3\u03b4 and \u03b1\u00df T cell subsets.<\/jats:p>","DOI":"10.3390\/cells10020373","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T17:20:38Z","timestamp":1613150438000},"page":"373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic Influence on the Peripheral Differentiation Signature of V\u03b42+ \u03b3\u03b4 and CD4+ \u03b1\u03b2 T Cells in Adults"],"prefix":"10.3390","volume":"10","author":[{"given":"Nicola","family":"Beucke","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Medical Center, 72072 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svenja","family":"Wingerter","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center, 72072 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"H\u00e4hnel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-0569","authenticated-orcid":false,"given":"Lisbeth Aagaard","family":"Larsen","sequence":"additional","affiliation":[{"name":"The Danish Twin Register, University of Southern Denmark, 5000 Odense C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaare","family":"Christensen","sequence":"additional","affiliation":[{"name":"The Danish Twin Register, University of Southern Denmark, 5000 Odense C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3600-0163","authenticated-orcid":false,"given":"Graham","family":"Pawelec","sequence":"additional","affiliation":[{"name":"Interfaculty Institute for Cell Biology, Department of Immunology, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Health Sciences North Research Institute, Sudbury, ON P3E 2H2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3104-8512","authenticated-orcid":false,"given":"Kilian","family":"Wistuba-Hamprecht","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center, 72072 T\u00fcbingen, Germany"},{"name":"Interfaculty Institute for Cell Biology, Department of Immunology, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s00281-020-00810-3","article-title":"The human immunosenescence phenotype: Does it exist?","volume":"42","author":"Pawelec","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3389\/fimmu.2013.00271","article-title":"Human T Cell Aging and the Impact of Persistent Viral Infections","volume":"4","author":"Fulop","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/path.4437","article-title":"The pathogenesis of human cytomegalovirus","volume":"235","author":"Griffiths","year":"2015","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12979-015-0052-x","article-title":"Peripheral blood T-cell signatures from high-resolution immune phenotyping of gamma delta and alpha beta T-cells in younger and older subjects in the Berlin Aging Study II","volume":"12","author":"Haehnel","year":"2015","journal-title":"Immun. Ageing"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/eji.1830210429","article-title":"A Major Fraction of Human Intraepithelial Lymphocytes Simultaneously Expresses the Gamma\/Delta T-Cell Receptor, the Cd8 Accessory Molecule and Preferentially Uses the V-Delta-1 Gene Segment","volume":"21","author":"Deusch","year":"1991","journal-title":"Eur. J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0092-8674(94)90170-8","article-title":"The nature of major histocompatibility complex recognition by gamma delta T cells","volume":"76","author":"Schild","year":"1994","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1073\/pnas.1621052114","article-title":"Sensing of cell stress by human gamma delta TCR-dependent recognition of annexin A2","volume":"114","author":"Marlin","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1002\/eji.201270101","article-title":"Gamma delta T-cell conference 2012: Close encounters for the fifth time","volume":"42","author":"Schamel","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1146\/annurev.immunol.18.1.975","article-title":"Gamma delta cells: A right time and a right place for a conserved third way of protection","volume":"18","author":"Hayday","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1159\/000086659","article-title":"Gamma delta T cells link innate and adaptive immune responses","volume":"86","author":"Holtmeier","year":"2005","journal-title":"Chem. Immunol. Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rampoldi, F., Ullrich, L., and Prinz, I. (2020). Revisiting the Interaction of gamma delta T-Cells and B-Cells. Cells, 9.","DOI":"10.3390\/cells9030743"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/eji.201142017","article-title":"IL-21 enhances the potential of human gamma delta T cells to provide B-cell help","volume":"42","author":"Bansal","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1126\/science.1110267","article-title":"Professional antigen-presentation function by human gamma delta T cells","volume":"309","author":"Brandes","year":"2005","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0008-8749(92)90008-D","article-title":"CD16 on human gamma delta T lymphocytes: Expression, function, and specificity for mouse IgG isotypes","volume":"143","author":"Braakman","year":"1992","journal-title":"Cell Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1038\/s41467-018-04076-0","article-title":"The human Vdelta2(+) T-cell compartment comprises distinct innate-like Vgamma9(+) and adaptive Vgamma9(-) subsets","volume":"9","author":"Davey","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14760","DOI":"10.1038\/ncomms14760","article-title":"Clonal selection in the human Vdelta1 T cell repertoire indicates gammadelta TCR-dependent adaptive immune surveillance","volume":"8","author":"Davey","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41568-019-0153-5","article-title":"Gammadelta T cells: Pleiotropic immune effectors with therapeutic potential in cancer","volume":"19","author":"Mensurado","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/cyto.a.22470","article-title":"OMIP-020: Phenotypic characterization of human gammadelta T-cells by multicolor flow cytometry","volume":"85","author":"Pawelec","year":"2014","journal-title":"Cytometry A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1742-4933-10-26","article-title":"Age-associated alterations in gammadelta T-cells are present predominantly in individuals infected with Cytomegalovirus","volume":"10","author":"Frasca","year":"2013","journal-title":"Immun. Ageing"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejca.2016.06.001","article-title":"Proportions of blood-borne Vdelta1+ and Vdelta2+ T-cells are associated with overall survival of melanoma patients treated with ipilimumab","volume":"64","author":"Martens","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-05849-1","article-title":"Ageing and latent CMV infection impact on maturation, differentiation and exhaustion profiles of T-cell receptor gammadelta T-cells","volume":"7","author":"Kallemeijn","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.4049\/jimmunol.1202940","article-title":"Differential impact of age and cytomegalovirus infection on the gammadelta T cell compartment","volume":"191","author":"Roux","year":"2013","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Xu, W., and Larbi, A. (2017). Markers of T Cell Senescence in Humans. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081742"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18649","DOI":"10.1073\/pnas.1922588117","article-title":"Microbial exposure drives polyclonal expansion of innate gammadelta T cells immediately after birth","volume":"117","author":"Ravens","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","first-page":"1537","article-title":"Genetic Influence on the Peripheral Blood CD4 + T-cell Differentiation Status in CMV Infection","volume":"71","author":"Goldeck","year":"2016","journal-title":"J. Gerontol. Ser. A Boil. Sci. Med. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1017\/thg.2019.72","article-title":"The Danish Twin Registry: An Updated Overview","volume":"22","author":"Pedersen","year":"2019","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1375\/136905203322296610","article-title":"Age- and sex-differences in the validity of questionnaire-based zygosity in twins","volume":"6","author":"Christiansen","year":"2003","journal-title":"Twin Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1365-2249.2008.03785.x","article-title":"Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals","volume":"155","author":"Chidrawar","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1099\/vir.0.036004-0","article-title":"Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans","volume":"92","author":"Derhovanessian","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1128\/JVI.79.6.3675-3683.2005","article-title":"Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8+ T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons","volume":"79","author":"Almanzar","year":"2005","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4618","DOI":"10.4049\/jimmunol.1001629","article-title":"Hallmark Features of Immunosenescence Are Absent in Familial Longevity","volume":"185","author":"Derhovanessian","year":"2010","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18638","DOI":"10.1073\/pnas.1922595117","article-title":"Fetal public Vgamma9Vdelta2 T cells expand and gain potent cytotoxic functions early after birth","volume":"117","author":"Papadopoulou","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fichtner, A.S., Ravens, S., and Prinz, I. (2020). Human gammadelta TCR Repertoires in Health and Disease. Cells, 9.","DOI":"10.3390\/cells9040800"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1189\/jlb.5A1213-650RR","article-title":"Gamma\/delta T cell subsets in human aging using the classical alpha\/beta T cell model","volume":"96","author":"Vasudev","year":"2014","journal-title":"J. Leukoc Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"44906","DOI":"10.18632\/oncotarget.10096","article-title":"Vdelta2+ and alpha\/ss T cells show divergent trajectories during human aging","volume":"7","author":"Tan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ebiom.2018.11.053","article-title":"Mapping of gamma\/delta T cells reveals Vdelta2+ T cells resistance to senescence","volume":"39","author":"Xu","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14378","DOI":"10.1073\/pnas.1611098113","article-title":"Heterogeneous yet stable V delta 2((+)) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals","volume":"113","author":"Ryan","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1084\/jem.20030235","article-title":"Differentiation of effector\/memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory sites","volume":"198","author":"Dieli","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1182\/blood-2008-01-136713","article-title":"Long-term expansion of effector\/memory Vdelta2-gammadelta T cells is a specific blood signature of CMV infection","volume":"112","author":"Pitard","year":"2008","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ni.3686","article-title":"Human gammadelta T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection","volume":"18","author":"Ravens","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2014.12.020","article-title":"Variation in the Human Immune System Is Largely Driven by Non-Heritable Influences","volume":"160","author":"Brodin","year":"2015","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13850","DOI":"10.1038\/ncomms13850","article-title":"Innate and adaptive immune traits are differentially affected by genetic and environmental factors","volume":"8","author":"Mangino","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_45","first-page":"927","article-title":"Establishing High Dimensional Immune Signatures from Peripheral Blood via Mass Cytometry in a Discovery Cohort of Stage IV Melanoma Patients","volume":"198","author":"Martens","year":"2016","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ejca.2016.12.011","article-title":"Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients","volume":"73","author":"Martens","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2797","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":"ref_48","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.4049\/jimmunol.178.7.4112","article-title":"Four functionally distinct populations of human effector-memory CD8+ T lymphocytes","volume":"178","author":"Romero","year":"2007","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1038\/s41588-020-0684-4","article-title":"Complex genetic signatures in immune cells underlie autoimmunity and inform therapy (vol 52, 1036, 2020)","volume":"52","author":"Orru","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cell.2015.02.046","article-title":"The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis","volume":"161","author":"Roederer","year":"2015","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/2\/373\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:22:57Z","timestamp":1760160177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/2\/373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,11]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["cells10020373"],"URL":"https:\/\/doi.org\/10.3390\/cells10020373","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,11]]}}}