{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T12:41:35Z","timestamp":1794055295304,"version":"4.8.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The ubiquitous Torque teno virus (TTV) establishes a chronically persistent infection in the human host. TTV has not been associated with any apparent disease, but, as part of the human virome, it may confer a regulatory imprint on the human immune system with as yet unclear consequences. However, so far, only few studies have characterized the TTV-specific immune responses or the overall immunological imprints by TTV. Here, we reveal that TTV infection leads to a highly exhausted TTV-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell response, hallmarked by decreased IFN-\u03b3 production and the expression of the inhibitory NKG2A-receptor. On a functional level, we identified a panel of highly polymorphic TTV-encoded peptides that lead to an expansion of regulatory NKG2A\n                    <jats:sup>+<\/jats:sup>\n                    natural killer, NKG2A\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    , and NKG2A\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells via the stabilization of the non-classical HLA-E molecule. Our results thus demonstrate that TTV leads to a distinct imprint on the human immune system that may further regulate overall human immune responses in infectious, autoimmune, and malignant diseases.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2024.1447980","type":"journal-article","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:45:20Z","timestamp":1725410720000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Torque teno viruses exhaust and imprint the human immune system via the HLA-E\/NKG2A axis"],"prefix":"10.3389","volume":"15","author":[{"given":"Hannes","family":"Vietzen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara","family":"Simonitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Friedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"K\u00fchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe L.","family":"Furlano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Florian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"G\u00f6rzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Koblischke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith H.","family":"Aberle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Puchhammer-St\u00f6ckl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","article-title":"Redefining chronic viral infection","volume":"138","author":"Virgin","year":"2009","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-021-05192-x","article-title":"Taxonomic update for mammalian anelloviruses (family Anelloviridae)","volume":"166","author":"Varsani","year":"2021","journal-title":"Arch Virol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-022-05516-5","article-title":"Recent changes to virus taxonomy ratified by the International Committee on Taxonomy of Viruses (2022)","volume":"167","author":"Walker","year":"2022","journal-title":"Arch Virol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuaa007","article-title":"Human anelloviruses: diverse, omnipresent and commensal members of the virome","volume":"44","author":"Kaczorowska","year":"2020","journal-title":"FEMS Microbiol Rev"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2020.01.011","article-title":"Assessment of prevalence and load of torquetenovirus viraemia in a large cohort of healthy blood donors","volume":"26","author":"Focosi","year":"2020","journal-title":"Clin Microbiol Infect."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111754","article-title":"Comprehensive profiling of antibody responses to the human anellome using programmable phage display","volume":"41","author":"Venkataraman","year":"2022","journal-title":"Cell Rep"},{"key":"B7","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/978-3-540-70972-5_5","article-title":"Immunobiology of the torque teno viruses and other anelloviruses","volume":"331","author":"Maggi","year":"2009","journal-title":"Curr Top Microbiol Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2013.12.007","article-title":"Plasma DNA levels of Torque teno virus and immunosuppression after lung transplantation","volume":"33","author":"Gorzer","year":"2014","journal-title":"J Heart Lung Transplant"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e0122975","DOI":"10.1371\/journal.pone.0122975","article-title":"Pre-transplant plasma Torque Teno virus load and increase dynamics after lung transplantation","volume":"10","author":"Gorzer","year":"2015","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.10356","article-title":"Effect of immune modulation on TT virus (TTV) and TTV-like-mini-virus (TLMV) viremia","volume":"70","author":"Moen","year":"2003","journal-title":"J Med Virol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.18773\/austprescr.2006.064","article-title":"Immunosuppressants - mechanisms of action and monitoring","volume":"4","author":"Pillans","year":"2006","journal-title":"Exp Clin Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e2034","DOI":"10.1002\/rmv.2034","article-title":"Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis","volume":"29","author":"Zuhair","year":"2019","journal-title":"Rev Med Virol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2217\/fvl.12.8","article-title":"The immune response to human CMV","volume":"7","author":"La Rosa","year":"2012","journal-title":"Future Virol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02410","article-title":"HLA-E peptide repertoire and dimorphism\u2014Centerpieces in the adaptive NK cell puzzle? [Perspective]","volume":"9","author":"R\u00f6lle","year":"2018","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0082-6","article-title":"Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells","volume":"19","author":"Hammer","year":"2018","journal-title":"Nat Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy452","article-title":"Torque teno virus as a novel biomarker targeting the efficacy of immunosuppression after lung transplantation","volume":"218","author":"Jaksch","year":"2018","journal-title":"J Infect Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.43.9.4807-4810.2005","article-title":"Relationships between total plasma load of torquetenovirus (TTV) and TTV genogroups carried","volume":"43","author":"Maggi","year":"2005","journal-title":"J Clin Microbiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.10564","article-title":"Distribution of TT virus genomic groups 1-5 in Brazilian blood donors, HBV carriers, and HIV-1-infected patients","volume":"72","author":"Devalle","year":"2004","journal-title":"J Med Virol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J Mol Biol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/tan.13439","article-title":"HLA-B*44:138Q: Evidence for a confined deletion and recombination events in an otherwise unaffected HLA-haplotype","volume":"93","author":"Fae","year":"2019","journal-title":"HLA"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41436-020-01077-7","article-title":"Deletion of the NKG2C receptor encoding KLRC2 gene and HLA-E variants are risk factors for severe COVID-19","volume":"26","author":"Vietzen","year":"2021","journal-title":"Genet Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0039.2009.01375.x","article-title":"A high-throughput Taqman approach for the discrimination of HLA-E alleles","volume":"74","author":"Paquay","year":"2009","journal-title":"Tissue Antigens"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0200428","DOI":"10.1371\/journal.pone.0200428","article-title":"Temporal dynamics of the lung and plasma viromes in lung transplant recipients","volume":"13","author":"Segura-Wang","year":"2018","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks438","article-title":"Immune epitope database analysis resource","volume":"40","author":"Kim","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B26","doi-asserted-by":"publisher","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":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.015","article-title":"Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis","volume":"186","author":"Vietzen","year":"2023","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1046\/j.1537-2995.2003.00312.x","article-title":"CMV DNA is rarely detected in healthy blood donors using validated PCR assays","volume":"43","author":"Roback","year":"2003","journal-title":"Transfusion"},{"key":"B29","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1002\/ijc.33859","article-title":"NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division","volume":"150","author":"Borst","year":"2022","journal-title":"Int J Cancer"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.75.24.11999-12004.2001","article-title":"Dynamics of persistent TT virus infection, as determined in patients treated with alpha interferon for concomitant hepatitis C virus infection","volume":"75","author":"Maggi","year":"2001","journal-title":"J Virol"},{"key":"B31","doi-asserted-by":"publisher","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":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.960852","article-title":"Implications of NKG2A in immunity and immune-mediated diseases","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e28759","DOI":"10.1002\/jmv.28759","article-title":"Association between human genetic variants affecting the host NK cell response and the development of herpes simplex virus type 1 encephalitis","volume":"95","author":"Graninger","year":"2023","journal-title":"J Med Virol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01155","article-title":"Subversion of immune response by human cytomegalovirus","volume":"10","author":"Patro","year":"2019","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-22834-1_12","article-title":"Immune evasion by epstein-barr virus","volume":"391","author":"Ressing","year":"2015","journal-title":"Curr Topics Microbiol Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1146\/annurev.med.53.082901.104053","article-title":"Viral persistence: HIV\u2019s strategies of immune system evasion","volume":"53","author":"Johnson","year":"2002","journal-title":"Annu Rev Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00682","article-title":"Papillomavirus immune evasion strategies target the infected cell and the local immune system","volume":"9","author":"Zhou","year":"2019","journal-title":"Front Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113872","article-title":"Integrative systems biology reveals NKG2A-biased immune responses correlate with protection in infectious disease, autoimmune disease, and cancer","volume":"43","author":"Chen","year":"2024","journal-title":"Cell Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1447980\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:45:22Z","timestamp":1725410722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1447980\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2024.1447980"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1447980","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,4]]},"article-number":"1447980"}}