{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T23:53:24Z","timestamp":1787961204254,"version":"build-2784847793"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010351","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI47206"],"award-info":[{"award-number":["AI47206"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006668","name":"Oregon Health and Science University","doi-asserted-by":"publisher","award":["Presidential Bridge Funding"],"award-info":[{"award-number":["Presidential Bridge Funding"]}],"id":[{"id":"10.13039\/100006668","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>CMV, a ubiquitous herpesvirus, elicits an extraordinarily large T cell response that is sustained or increases over time, a phenomenon termed \u2018memory inflation.\u2019 Remarkably, even latent, non-productive infection can drive memory inflation. Despite intense research on this phenomenon, the infected cell type(s) involved are unknown. To identify the responsible cell type(s), we designed a <jats:italic>Cre-lox<\/jats:italic> murine CMV (MCMV) system, where a spread-deficient (\u0394gL) virus expresses recombinant SIINFEKL only in Cre<jats:sup>+<\/jats:sup> host cells. We found that latent infection of endothelial cells (ECs), but not dendritic cells (DCs) or hepatocytes, was sufficient to drive CD8 T cell memory inflation. Infection of Lyve-1-Cre and Prox1-CreER<jats:sup>T2<\/jats:sup> mice revealed that amongst EC subsets, infection of lymphatic ECs was sufficient. Genetic ablation of \u03b22m on lymphatic ECs did not prevent inflation, suggesting another unidentified cell type can also present antigen to CD8 T cells during latency. This novel system definitively shows that antigen presentation by lymphatic ECs drives robust CD8 T cell memory inflation.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010351","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T18:38:55Z","timestamp":1674499135000},"page":"e1010351","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Latent CMV infection of Lymphatic endothelial cells is sufficient to drive CD8 T cell memory inflation"],"prefix":"10.1371","volume":"19","author":[{"given":"Michael W.","family":"Munks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Rott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlo A.","family":"Nesterenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savannah M.","family":"Smart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venasha","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Tatum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangwu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tameka","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8962-5896","authenticated-orcid":true,"given":"Ann B.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"ppat.1010351.ref001","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":"P Brodin","journal-title":"Cell"},{"key":"ppat.1010351.ref002","doi-asserted-by":"crossref","first-page":"11495","DOI":"10.1128\/JVI.74.24.11495-11503.2000","article-title":"Enrichment of immediate-early 1 (m123\/pp89) peptide-specific CD8 T cells in a pulmonary CD62L(lo) memory-effector cell pool during latent murine cytomegalovirus infection of the lungs","volume":"74","author":"R Holtappels","year":"2000","journal-title":"J. Virol"},{"key":"ppat.1010351.ref003","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":"U Karrer","year":"2003","journal-title":"J Immunol"},{"key":"ppat.1010351.ref004","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1128\/JVI.78.11.5535-5545.2004","article-title":"Memory CD8 T-cell differentiation during viral infection","volume":"78","author":"EJ Wherry","year":"2004","journal-title":"J Virol"},{"key":"ppat.1010351.ref005","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/ni1241","article-title":"T cells and viral persistence: lessons from diverse infections","volume":"6","author":"P Klenerman","year":"2005","journal-title":"Nat Immunol"},{"key":"ppat.1010351.ref006","doi-asserted-by":"crossref","first-page":"e1002889","DOI":"10.1371\/journal.ppat.1002889","article-title":"Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years","volume":"8","author":"PL Klarenbeek","year":"2012","journal-title":"PLoS Pathog"},{"key":"ppat.1010351.ref007","doi-asserted-by":"crossref","first-page":"e0226705","DOI":"10.1371\/journal.pone.0226705","article-title":"Cross-presentation of a spread-defective MCMV is sufficient to prime the majority of virus-specific CD8+ T cells","volume":"14","author":"CM Snyder","year":"2019","journal-title":"PLoS One"},{"key":"ppat.1010351.ref008","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00430-012-0273-y","article-title":"Viral latency drives \u2019memory inflation\u2019: a unifying hypothesis linking two hallmarks of cytomegalovirus infection","volume":"201","author":"CK Seckert","year":"2012","journal-title":"Med. Microbiol. Immunol"},{"key":"ppat.1010351.ref009","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nri.2016.38","article-title":"T cell responses to cytomegalovirus","volume":"16","author":"P Klenerman","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"ppat.1010351.ref010","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/imr.12653","article-title":"The (gradual) rise of memory inflation","volume":"283","author":"P Klenerman","year":"2018","journal-title":"Immunol Rev"},{"key":"ppat.1010351.ref011","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.4049\/jimmunol.1800171","article-title":"Cytomegalovirus: Shape-Shifting the Immune System.","volume":"200","author":"G Picarda","year":"2018","journal-title":"J Immunol"},{"key":"ppat.1010351.ref012","first-page":"339","article-title":"Cytomegalovirus memory inflation and immune protection","volume":"208","author":"L. Cicin-Sain","year":"2019"},{"key":"ppat.1010351.ref013","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3389\/fimmu.2019.00197","article-title":"Inflation vs. Exhaustion of Antiviral CD8+ T-Cell Populations in Persistent Infections: Two Sides of the Same Coin?","volume":"10","author":"E Marchi","year":"2019","journal-title":"Front Immunol."},{"key":"ppat.1010351.ref014","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":"SPH van den Berg","year":"2019","journal-title":"Med Microbiol Immunol"},{"key":"ppat.1010351.ref015","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00430-019-00587-9","article-title":"Fuel and brake of memory T cell inflation","volume":"208","author":"SPM Welten","year":"2019","journal-title":"Med Microbiol Immunol"},{"key":"ppat.1010351.ref016","doi-asserted-by":"crossref","first-page":"731","DOI":"10.3390\/pathogens10060731","article-title":"Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection","volume":"10","author":"NAW Lemmermann","year":"2021","journal-title":"Pathogens"},{"key":"ppat.1010351.ref017","doi-asserted-by":"crossref","first-page":"7235","DOI":"10.4049\/jimmunol.178.11.7235","article-title":"Viral interference with antigen presentation does not alter acute or chronic CD8 T cell immunodominance in murine cytomegalovirus infection","volume":"178","author":"MW Munks","year":"2007","journal-title":"J Immunol"},{"key":"ppat.1010351.ref018","doi-asserted-by":"crossref","first-page":"668885","DOI":"10.3389\/fimmu.2021.668885","article-title":"Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell \"Memory Inflation\" and Avoid Immune Evasion","volume":"12","author":"M Griessl","year":"2021","journal-title":"Front Immunol"},{"key":"ppat.1010351.ref019","doi-asserted-by":"crossref","first-page":"10436","DOI":"10.1128\/JVI.01248-06","article-title":"CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation","volume":"80","author":"CO Simon","year":"2006","journal-title":"J Virol"},{"key":"ppat.1010351.ref020","doi-asserted-by":"crossref","first-page":"e1002313","DOI":"10.1371\/journal.ppat.1002313","article-title":"Non-hematopoietic cells in lymph nodes drive memory CD8 T cell inflation during murine cytomegalovirus infection","volume":"7","author":"N Torti","year":"2011","journal-title":"PLoS Pathog"},{"key":"ppat.1010351.ref021","doi-asserted-by":"crossref","first-page":"e1004233","DOI":"10.1371\/journal.ppat.1004233","article-title":"Systemic hematogenous maintenance of memory inflation by MCMV infection","volume":"10","author":"CJ Smith","year":"2014","journal-title":"PLoS Pathog"},{"key":"ppat.1010351.ref022","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1128\/jvi.62.3.987-997.1988","article-title":"Pathogenesis of Murine Cytomegalovirus Infection: Identification of Infected Cells in the Spleen during Acute and Latent Infections","volume":"62","author":"JA Mercer","year":"1988","journal-title":"J Virol"},{"key":"ppat.1010351.ref023","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00430-019-00592-y","article-title":"Cellular reservoirs of latent cytomegaloviruses","volume":"208","author":"MJ Reddehase","year":"2019","journal-title":"Med Microbiol Immunol"},{"key":"ppat.1010351.ref024","doi-asserted-by":"crossref","first-page":"8869","DOI":"10.1128\/JVI.00870-09","article-title":"Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation","volume":"83","author":"CK Seckert","year":"2009","journal-title":"J Virol"},{"key":"ppat.1010351.ref025","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.4049\/jimmunol.1203151","article-title":"Competition for antigen at the level of the APC is a major determinant of immunodominance during memory inflation in murine cytomegalovirus infection","volume":"190","author":"LA Farrington","year":"2013","journal-title":"J Immunol"},{"key":"ppat.1010351.ref026","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.chom.2008.02.014","article-title":"The major virus-producing cell type during murine cytomegalovirus infection, the hepatocyte, is not the source of virus dissemination in the host","volume":"3","author":"T Sacher","year":"2008","journal-title":"Cell Host Microbe"},{"key":"ppat.1010351.ref027","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1099\/vir.0.006668-0","article-title":"Murine cytomegalovirus displays selective infection of cells within hours after systemic administration","volume":"90","author":"KM Hsu","year":"2009","journal-title":"J Gen Virol"},{"key":"ppat.1010351.ref028","first-page":"8079","article-title":"LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis","volume":"61","author":"C Mouta Carreira","year":"2001","journal-title":"Cancer Res"},{"key":"ppat.1010351.ref029","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1172\/JCI58050","article-title":"Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice","volume":"121","author":"E Bazigou","year":"2011","journal-title":"J Clin Invest"},{"key":"ppat.1010351.ref030","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/76996","article-title":"Wigle JT, and Oliver G. Hepatocyte migration during liver development requires Prox1","volume":"25","author":"B. Sosa-Pineda","year":"2000","journal-title":"Nat Genet"},{"key":"ppat.1010351.ref031","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/j.ajpath.2011.12.026","article-title":"ProxTom lymphatic vessel reporter mice reveal Prox1 expression in the adrenal medulla, megakaryocytes, and platelets","volume":"180","author":"LA Truman","year":"2012","journal-title":"Am J Pathol"},{"key":"ppat.1010351.ref032","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.stem.2008.09.018","article-title":"Fate tracing reveals the endothelial origin of hematopoietic stem cells","volume":"3","author":"AC Zovein","year":"2008","journal-title":"Cell stem cell"},{"key":"ppat.1010351.ref033","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/351402a0","article-title":"Peptide-induced conformational change of the class I heavy chain","volume":"351","author":"T Elliott","year":"1991","journal-title":"Nature"},{"key":"ppat.1010351.ref034","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/ni1058","article-title":"Huppa, JB and Davis MM. T cell killing does not require the formation of a stable mature immunological synapse","volume":"5","author":"MA Purbhoo","year":"2004","journal-title":"Nat Immunol"},{"key":"ppat.1010351.ref035","first-page":"681","article-title":"Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation","volume":"207","author":"JN Cohen","year":"2010"},{"key":"ppat.1010351.ref036","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.4049\/jimmunol.1302492","article-title":"Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells","volume":"192","author":"S Hirosue","year":"2014","journal-title":"J Immunol"},{"key":"ppat.1010351.ref037","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1084\/jem.20180654","article-title":"IFNgamma-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin","volume":"215","author":"RS Lane","year":"2018","journal-title":"J Exp Med"},{"key":"ppat.1010351.ref038","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.4049\/jimmunol.0900227","article-title":"CD4+ T cell help has an epitope-dependent impact on CD8+ T cell memory inflation during murine cytomegalovirus infection","volume":"183","author":"CM Snyder","year":"2009","journal-title":"J Immunol"},{"key":"ppat.1010351.ref039","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1002\/eji.201141575","article-title":"T-cell help permits memory CD8(+) T-cell inflation during cytomegalovirus latency","volume":"41","author":"SM Walton","year":"2011","journal-title":"Eur J Immunol"},{"key":"ppat.1010351.ref040","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1002\/eji.200940256","article-title":"Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells","volume":"40","author":"IR Humphreys","year":"2010","journal-title":"Eur J Immunol"},{"key":"ppat.1010351.ref041","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.4049\/jimmunol.179.4.2195","article-title":"OX40 costimulation promotes persistence of cytomegalovirus-specific CD8 T Cells: A CD4-dependent mechanism","volume":"179","author":"IR Humphreys","year":"2007","journal-title":"J Immunol"},{"key":"ppat.1010351.ref042","doi-asserted-by":"crossref","first-page":"6851","DOI":"10.1128\/JVI.03305-12","article-title":"CD27-CD70 costimulation controls T cell immunity during acute and persistent cytomegalovirus infection","volume":"87","author":"SP Welten","year":"2013","journal-title":"J Virol"},{"key":"ppat.1010351.ref043","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s00430-019-00605-w","article-title":"Impact of CMV upon immune ageing: facts and fiction","volume":"208","author":"M Jergovic","year":"2019","journal-title":"Med Microbiol Immunol"},{"key":"ppat.1010351.ref044","doi-asserted-by":"crossref","first-page":"7056","DOI":"10.1128\/JVI.73.8.7056-7060.1999","article-title":"Systematic excision of vector sequences from the BAC-cloned herpesvirus genome during virus reconstitution","volume":"73","author":"M Wagner","year":"1999","journal-title":"J Virol"},{"key":"ppat.1010351.ref045","doi-asserted-by":"crossref","first-page":"14759","DOI":"10.1073\/pnas.94.26.14759","article-title":"Ziegler, H and Koszinowski UH. Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome","volume":"94","author":"M Messerle","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1010351.ref046","article-title":"Use of bacterial artificial chromosomes in generating targeted mutations in human and mouse cytomegaloviruses","author":"EM Borst","year":"2007","journal-title":"Current protocols in immunology"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1010351","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1010351","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T19:57:31Z","timestamp":1675367851000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1010351"}},"subtitle":[],"editor":[{"given":"Robert F.","family":"Kalejta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,23]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1010351","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1010351","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,23]]}}}