{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:16:05Z","timestamp":1765808165646,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T00:00:00Z","timestamp":1678752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006342","name":"Association Gr\u00e9gory Lemarchal","doi-asserted-by":"publisher","award":["RF20190502487","LSC 10280","17-RHUS-0010"],"award-info":[{"award-number":["RF20190502487","LSC 10280","17-RHUS-0010"]}],"id":[{"id":"10.13039\/501100006342","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Institut de recherche en Sant\u00e9 Respiratoire des Pays de la Loire (France)","award":["RF20190502487","LSC 10280","17-RHUS-0010"],"award-info":[{"award-number":["RF20190502487","LSC 10280","17-RHUS-0010"]}]},{"DOI":"10.13039\/501100001665","name":"Kidney Transplantation Diagnostics Innovation (KTD Innov)","doi-asserted-by":"publisher","award":["RF20190502487","LSC 10280","17-RHUS-0010"],"award-info":[{"award-number":["RF20190502487","LSC 10280","17-RHUS-0010"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>This study investigated the frequency and peptide specificity of long-lasting HCMV-specific CD8 T cells in a cohort of 120 cytomegalovirus seropositive (HCMV+) healthy carriers with the aim of deciphering the relative contribution of unconventional HLA-E- versus conventional HLA-A2-specific CD8 T cells to long-term T cell memory expansion in HCMV immunity. The presence of HCMV-specific CD8 T cells was investigated by flow cytometry using five MHC\/peptide tetramer complexes (HLA-A2\/pp65, HLA-A2\/IE1 and three different HLA-E\/UL40). Here, we report that 50% of HCMV+ healthy individuals possess HCMV-specific CD8 T cells, representing \u22650.1% of total blood CD8 T cells years post-infection. Around a third (30.8%) of individuals possess HLA-A2-restricted (A2pp65 or A2IE1) and an equal proportion (27.5%) possess an HLA-E\/UL40 CD8 T response. Concomitant HLA-E- and HLA-A2-reactive CD8 T cells were frequently found, and VMAPRTLIL peptide was the major target. The frequency of HLA-E\/VMAPRTLIL among total blood CD8 T cells was significantly higher than the frequency of HLA-A2pp65 T cells (mean values: 5.9% versus 2.3%, p = 0.0354). HLA-EUL40 CD8 T cells display lower TCR avidity but similar levels of CD3 and CD8 coreceptors. In conclusion, HLA-E-restricted CD8 T cells against the VMAPRTLIL UL40 peptide constitute a predominant subset among long-lasting anti-HCMV CD8 T cells.<\/jats:p>","DOI":"10.3390\/cells12060889","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T03:29:16Z","timestamp":1678764556000},"page":"889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Persistent CD8 T Cell Marks Caused by the HCMV Infection in Seropositive Adults: Prevalence of HLA-E-Reactive CD8 T Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Am\u00e9lie","family":"Rousseli\u00e8re","sequence":"first","affiliation":[{"name":"Centre de Recherche Translationnelle en Transplantation et Immunologie (CR2TI), Nantes Universit\u00e9, CHU Nantes, Inserm, UMR 1064, 44093 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5870-4615","authenticated-orcid":false,"given":"B\u00e9atrice","family":"Charreau","sequence":"additional","affiliation":[{"name":"Centre de Recherche Translationnelle en Transplantation et Immunologie (CR2TI), Nantes Universit\u00e9, CHU Nantes, Inserm, UMR 1064, 44093 Nantes, France"},{"name":"CHU Nantes, Institut de Transplantation Urologie N\u00e9phrologie (ITUN), CEDEX 1, 44093 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1182\/blood.V95.7.2240","article-title":"Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation","volume":"95","author":"Broers","year":"2000","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.3389\/fmicb.2015.01016","article-title":"Ongoing burden of disease and mortality from HIV\/CMV coinfection in Africa in the antiretroviral therapy era","volume":"6","author":"Adland","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1111\/ajt.13791","article-title":"The Cell Biology of Cytomegalovirus: Implications for Transplantation","volume":"16","author":"Kaminski","year":"2016","journal-title":"Am. J. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/rmv.655","article-title":"Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection","volume":"20","author":"Cannon","year":"2010","journal-title":"Rev. Med. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ejogrb.2020.12.006","article-title":"Cytomegalovirus infection in pregnancy\u2014An update","volume":"258","author":"Navti","year":"2021","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0923-1811(99)00085-7","article-title":"Current understanding of cytomegalovirus infection in immunocompetent individuals","volume":"22","author":"Kano","year":"2000","journal-title":"J. Dermatol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chiereghin, A., Verucchi, G., and Lazzarotto, T. (2021). CMV-Specific Cell-Mediated Immunity in Immunocompetent Adults with Primary CMV Infection: A Case Series and Review of the Literature. Viruses, 13.","DOI":"10.3390\/v13050816"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00430-019-00608-7","article-title":"The hallmarks of CMV-specific CD8 T-cell differentiation","volume":"208","author":"Pardieck","year":"2019","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nri.2016.38","article-title":"T cell responses to cytomegalovirus","volume":"16","author":"Klenerman","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14725","DOI":"10.1073\/pnas.1110900108","article-title":"Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection","volume":"108","author":"Milush","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.4049\/jimmunol.170.4.2022","article-title":"Memory inflation: Continuous accumulation of antiviral CD8+ T cells over time","volume":"170","author":"Karrer","year":"2003","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.4049\/jimmunol.176.4.2645","article-title":"Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly","volume":"176","author":"Hadrup","year":"2006","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.virusres.2010.09.010","article-title":"Role of CMV in immune senescence","volume":"157","author":"Pawelec","year":"2011","journal-title":"Virus Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.exger.2014.03.020","article-title":"New advances in CMV and immunosenescence","volume":"55","author":"Sansoni","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/acel.12059","article-title":"Cytomegalovirus infection is associated with increased mortality in the older population","volume":"12","author":"Savva","year":"2013","journal-title":"Aging Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/qjmed\/hcw026","article-title":"Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals","volume":"109","author":"Firth","year":"2016","journal-title":"QJM"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1593\/neo.81178","article-title":"The story of human cytomegalovirus and cancer: Increasing evidence and open questions","volume":"11","author":"Michaelis","year":"2009","journal-title":"Neoplasia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8179","DOI":"10.1128\/JVI.73.10.8179-8184.1999","article-title":"Target structures of the CD8(+)-T-cell response to human cytomegalovirus: The 72-kilodalton major immediate-early protein revisited","volume":"73","author":"Kern","year":"1999","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1128\/JVI.73.3.2099-2108.1999","article-title":"The memory cytotoxic T-lymphocyte (CTL) response to human cytomegalovirus infection contains individual peptide-specific CTL clones that have undergone extensive expansion in vivo","volume":"73","author":"Weekes","year":"1999","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1084\/jem.20050882","article-title":"Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects","volume":"202","author":"Sylwester","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mad.2016.03.002","article-title":"A new perspective of the structural complexity of HCMV-specific T-cell responses","volume":"158","author":"Sylwester","year":"2016","journal-title":"Mech. Ageing Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/35869","article-title":"HLA-E binds to natural killer cell receptors CD94\/NKG2A, B and C","volume":"391","author":"Braud","year":"1998","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1084\/jem.20072525","article-title":"CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence","volume":"205","author":"Petrie","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3687","DOI":"10.1002\/1521-4141(200112)31:12<3687::AID-IMMU3687>3.0.CO;2-C","article-title":"The analysis of the natural killer-like activity of human cytolytic T lymphocytes revealed HLA-E as a novel target for TCR alpha\/beta-mediated recognition","volume":"31","author":"Pietra","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11328","DOI":"10.1073\/pnas.172369799","article-title":"Identification of HLA-E-specific alloreactive T lymphocytes: A cell subset that undergoes preferential expansion in mixed lymphocyte culture and displays a broad cytolytic activity against allogeneic cells","volume":"99","author":"Romagnani","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ni1312","article-title":"Structural basis for a major histocompatibility complex class Ib-restricted T cell response","volume":"7","author":"Hoare","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Allard, M., Tonnerre, P., Nedellec, S., Oger, R., Morice, A., Guilloux, Y., Houssaint, E., Charreau, B., and Gervois, N. (2012). HLA-E-restricted cross-recognition of allogeneic endothelial cells by CMV-associated CD8 T cells: A potential risk factor following transplantation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050951"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sullivan, L.C., Westall, G.P., Widjaja, J.M., Mifsud, N.A., Nguyen, T.H., Meehan, A.C., Kotsimbos, T.C., and Brooks, A.G. (2015). The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135972"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Jouand, N., Bressollette-Bodin, C., Gerard, N., Giral, M., Guerif, P., Rodallec, A., Oger, R., Parrot, T., Allard, M., and Cesbron-Gautier, A. (2018). HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007041"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1063690","DOI":"10.3389\/fimmu.2022.1063690","article-title":"Distinctive phenotype for HLA-E- versus HLA-A2-restricted memory CD8 alphabetaT cells in the course of HCMV infection discloses features shared with NKG2C(+)CD57(+)NK and delta2(-)gammadeltaT cell subsets","volume":"13","author":"Rousseliere","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1097\/TP.0b013e3181859edd","article-title":"UL40 human cytomegalovirus variability evolution patterns over time in renal transplant recipients","volume":"86","author":"Garrigue","year":"2008","journal-title":"Transplantation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8679","DOI":"10.1074\/jbc.M112.409672","article-title":"Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells","volume":"288","author":"Heatley","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e02996-20","DOI":"10.1128\/mBio.02996-20","article-title":"Extent of Cytomegalovirus Replication in the Human Host Depends on Variations of the HLA-E\/UL40 Axis","volume":"12","author":"Vietzen","year":"2021","journal-title":"mBio"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/76292","article-title":"Efficient detection and immunomagnetic sorting of specific T cells using multimers of MHC class I and peptide with reduced CD8 binding","volume":"6","author":"Bodinier","year":"2000","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Colugnati, F.A., Staras, S.A., Dollard, S.C., and Cannon, M.J. (2007). Incidence of cytomegalovirus infection among the general population and pregnant women in the United States. BMC Infect. Dis., 7.","DOI":"10.1186\/1471-2334-7-71"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6973","DOI":"10.1073\/pnas.1221609110","article-title":"T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy","volume":"110","author":"Zhong","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Geisler, J., Touma, J., Rahbar, A., Soderberg-Naucler, C., and Vetvik, K. (2019). A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity. Cancers, 11.","DOI":"10.3390\/cancers11121842"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/eji.1830270517","article-title":"The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9","volume":"27","author":"Braud","year":"1997","journal-title":"Eur. J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S1074-7613(02)00427-2","article-title":"TCR specificity dictates CD94\/NKG2A expression by human CTL","volume":"17","author":"Jabri","year":"2002","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tarrago, D., Gonzalez, I., and Gonzalez-Escribano, M.F. (2022). HLA-E restricted cytomegalovirus UL40 peptide polymorphism may represent a risk factor following congenital infection. BMC Genom., 23.","DOI":"10.1186\/s12864-022-08689-0"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1002\/eji.200636765","article-title":"Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region","volume":"37","author":"Wooldridge","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15232","DOI":"10.1074\/jbc.275.20.15232","article-title":"Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha","volume":"275","author":"Gao","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.4049\/jimmunol.1700242","article-title":"Peptide-MHC Class I Tetramers Can Fail To Detect Relevant Functional T Cell Clonotypes and Underestimate Antigen-Reactive T Cell Populations","volume":"200","author":"Rius","year":"2018","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7194","DOI":"10.1038\/s41598-020-64133-x","article-title":"Lack of cytomegalovirus (CMV)-specific cell-mediated immune response using QuantiFERON-CMV assay in CMV-seropositive healthy volunteers: Fact not artifact","volume":"10","author":"Aguado","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1074\/jbc.M208268200","article-title":"HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities","volume":"278","author":"Strong","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1080\/14712598.2021.1857720","article-title":"Cell therapy for cytomegalovirus infection","volume":"21","author":"Neill","year":"2021","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1182\/blood-2006-06-030213","article-title":"Expression and release of soluble HLA-E is an immunoregulatory feature of endothelial cell activation","volume":"109","author":"Coupel","year":"2007","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"907092","DOI":"10.1155\/2010\/907092","article-title":"The emerging role of HLA-E-restricted CD8+ T lymphocytes in the adaptive immune response to pathogens and tumors","volume":"2010","author":"Pietra","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eabe6968","DOI":"10.1126\/sciimmunol.abe6968","article-title":"Human cytomegalovirus expands a CD8(+) T cell population with loss of BCL11B expression and gain of NK cell identity","volume":"6","author":"Sottile","year":"2021","journal-title":"Sci. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/6\/889\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:54:28Z","timestamp":1760122468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/6\/889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,14]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cells12060889"],"URL":"https:\/\/doi.org\/10.3390\/cells12060889","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2023,3,14]]}}}