{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T02:26:26Z","timestamp":1777775186832,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014150","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000}}],"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1713 project number 534829736"],"award-info":[{"award-number":["SFB1713 project number 534829736"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STA 1549\/1-2"],"award-info":[{"award-number":["STA 1549\/1-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BR 1730\/9-1"],"award-info":[{"award-number":["BR 1730\/9-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017519","name":"Werner Otto Stiftung","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/501100017519","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Faculty of the University of Hamburg","award":["na"],"award-info":[{"award-number":["na"]}]},{"name":"UKE - Universit\u00e4tsklinikum Hamburg-Eppendorf"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Differential antiviral T cell immunity in early life impacts the clinical outcome of Cytomegalovirus (CMV) infection, but the underlying mechanisms are not well understood. T cells are known to be involved in protection from CMV disease. To further elucidate these mechanisms, we used a model of respiratory murine CMV (MCMV) infection and adoptive T cell transfers to characterize MCMV-specific T cell responses in early life. We analyzed the effector T cell differentiation using single-cell RNA sequencing and assessed the local pulmonary cytokine milieu. We found delayed enrichment of early-life murine MCMV-specific CD8 T cells due to a general deficiency of \u03b1\u03b2 T cells. Adoptive transfer of na\u00efve adult T cells into neonates did not protect from lung MCMV infection due to generation of non-cytotoxic CD8 effector T cells. Furthermore, key cytokines required for effective CD8 T cell priming were absent in early life. Supplementation with these cytokines enhanced infection control by transferred adult T cells. The effector function of adult-primed T cells was not disrupted in neonates. Together, this study suggests defective CD8 T cell priming in neonates as a factor explaining the higher risk for MCMV lung disease in the early-life phase.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014150","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T17:49:44Z","timestamp":1776707384000},"page":"e1014150","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Limited protection against early-life lung murine cytomegalovirus infection results from deficiency of cytotoxic CD8 T cells"],"prefix":"10.1371","volume":"22","author":[{"given":"Lu\u00eds Fonseca","family":"Brito","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonore","family":"Ostermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"T\u00f6dter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanamjeet","family":"Virdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Indenbirken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renke","family":"Brixel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramon","family":"Arens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Grundhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfram","family":"Brune","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-8967","authenticated-orcid":true,"given":"Felix Rolf","family":"Stahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"issue":"9","key":"ppat.1014150.ref001","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/nri3277","article-title":"The impact of differential antiviral immunity in children and adults","volume":"12","author":"AJ Prendergast","year":"2012","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"ppat.1014150.ref002","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1084\/jem.20071489","article-title":"Altered development of the brain after focal herpesvirus infection of the central nervous system","volume":"205","author":"T Koontz","year":"2008","journal-title":"J Exp Med"},{"issue":"6","key":"ppat.1014150.ref003","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/infdis\/148.6.953","article-title":"Specific cell-mediated immunity and the natural history of congenital infection with cytomegalovirus","volume":"148","author":"RF Pass","year":"1983","journal-title":"J Infect Dis"},{"issue":"12","key":"ppat.1014150.ref004","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41579-021-00582-z","article-title":"Pathogenesis of human cytomegalovirus in the immunocompromised host","volume":"19","author":"P Griffiths","year":"2021","journal-title":"Nat Rev Microbiol"},{"issue":"6","key":"ppat.1014150.ref005","doi-asserted-by":"crossref","DOI":"10.1016\/S1473-3099(17)30143-3","article-title":"Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy","volume":"17","author":"WD Rawlinson","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"ppat.1014150.ref006","doi-asserted-by":"crossref","DOI":"10.1093\/infdis\/jiz493","article-title":"Advances in the Development of Therapeutics for Cytomegalovirus Infections","volume":"221","author":"E Acosta","year":"2020","journal-title":"J Infect Dis"},{"issue":"10","key":"ppat.1014150.ref007","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/S1473-3099(12)70197-4","article-title":"Burden of disease associated with human cytomegalovirus and prospects for elimination by universal immunisation","volume":"12","author":"PD Griffiths","year":"2012","journal-title":"Lancet Infect Dis"},{"issue":"6","key":"ppat.1014150.ref008","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"},{"issue":"5","key":"ppat.1014150.ref009","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2018.06.045","article-title":"Stereotypic Immune System Development in Newborn Children","volume":"174","author":"A Olin","year":"2018","journal-title":"Cell"},{"issue":"11","key":"ppat.1014150.ref010","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1172\/JCI200317470","article-title":"Mature CD8(+) T lymphocyte response to viral infection during fetal life","volume":"111","author":"A Marchant","year":"2003","journal-title":"J Clin Invest"},{"issue":"4","key":"ppat.1014150.ref011","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.4049\/jimmunol.1501867","article-title":"The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection","volume":"196","author":"V Venturi","year":"2016","journal-title":"J Immunol"},{"issue":"3","key":"ppat.1014150.ref012","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.4049\/jimmunol.181.3.2111","article-title":"CD8+ T lymphocytes control murine cytomegalovirus replication in the central nervous system of newborn animals","volume":"181","author":"GRB Bantug","year":"2008","journal-title":"J Immunol"},{"issue":"12","key":"ppat.1014150.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003828","article-title":"Nodular inflammatory foci are sites of T cell priming and control of murine cytomegalovirus infection in the neonatal lung","volume":"9","author":"FR Stahl","year":"2013","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1014150.ref014","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/mi.2014.42","article-title":"Mck2-dependent infection of alveolar macrophages promotes replication of MCMV in nodular inflammatory foci of the neonatal lung","volume":"8","author":"FR Stahl","year":"2015","journal-title":"Mucosal Immunol"},{"issue":"16","key":"ppat.1014150.ref015","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.3390\/ijms20163865","article-title":"Cytomegalovirus (CMV) Pneumonitis: Cell Tropism, Inflammation, and Immunity","volume":"20","author":"L Fonseca Brito","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"8","key":"ppat.1014150.ref016","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1007252","article-title":"Control of primary mouse cytomegalovirus infection in lung nodular inflammatory foci by cooperation of interferon-gamma expressing CD4 and CD8 T cells","volume":"14","author":"Y Lueder","year":"2018","journal-title":"PLoS Pathog"},{"key":"ppat.1014150.ref017","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1099\/vir.0.029827-0","article-title":"Single cell detection of latent cytomegalovirus reactivation in host tissue","volume":"92","author":"A Marquardt","year":"2011","journal-title":"J Gen Virol"},{"issue":"6","key":"ppat.1014150.ref018","doi-asserted-by":"crossref","first-page":"112597","DOI":"10.1016\/j.celrep.2023.112597","article-title":"MCK2-mediated MCMV infection of macrophages and virus dissemination to the salivary gland depends on MHC class I molecules","volume":"42","author":"B Bo\u0161njak","year":"2023","journal-title":"Cell Rep"},{"issue":"19","key":"ppat.1014150.ref019","doi-asserted-by":"crossref","first-page":"10346","DOI":"10.1128\/JVI.00545-11","article-title":"Virus progeny of murine cytomegalovirus bacterial artificial chromosome pSM3fr show reduced growth in salivary Glands due to a fixed mutation of MCK-2","volume":"85","author":"S Jordan","year":"2011","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014150.ref020","doi-asserted-by":"crossref","first-page":"450","DOI":"10.4049\/jimmunol.177.1.450","article-title":"Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection","volume":"177","author":"MW Munks","year":"2006","journal-title":"J Immunol"},{"issue":"5","key":"ppat.1014150.ref021","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.01986-23","article-title":"Virological, innate, and adaptive immune profiles shaped by variation in route and age of host in murine cytomegalovirus infection","volume":"98","author":"CP Coplen","year":"2024","journal-title":"J Virol"},{"key":"ppat.1014150.ref022","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.3389\/fimmu.2019.01358","article-title":"Investigating the Dynamics of MCMV-Specific CD8+ T Cell Responses in Individual Hosts","volume":"10","author":"M Gabel","year":"2019","journal-title":"Front Immunol"},{"issue":"10","key":"ppat.1014150.ref023","doi-asserted-by":"crossref","first-page":"6472","DOI":"10.4049\/jimmunol.180.10.6472","article-title":"Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell response","volume":"180","author":"R Arens","year":"2008","journal-title":"J Immunol"},{"issue":"1","key":"ppat.1014150.ref024","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20202343","article-title":"Dependence on Bcl6 and Blimp1 drive distinct differentiation of murine memory and follicular helper CD4+ T cells","volume":"219","author":"T Ciucci","year":"2022","journal-title":"J Exp Med"},{"key":"ppat.1014150.ref025","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.76339","article-title":"A CD4+ T cell reference map delineates subtype-specific adaptation during acute and chronic viral infections","volume":"11","author":"M Andreatta","year":"2022","journal-title":"Elife"},{"issue":"8","key":"ppat.1014150.ref026","doi-asserted-by":"crossref","first-page":"108078","DOI":"10.1016\/j.celrep.2020.108078","article-title":"Landscape of Exhausted Virus-Specific CD8 T Cells in Chronic LCMV Infection","volume":"32","author":"I Sandu","year":"2020","journal-title":"Cell Rep"},{"issue":"1","key":"ppat.1014150.ref027","doi-asserted-by":"crossref","first-page":"1737369","DOI":"10.1080\/2162402X.2020.1737369","article-title":"Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq","volume":"9","author":"SJ Carmona","year":"2020","journal-title":"Oncoimmunology"},{"issue":"1","key":"ppat.1014150.ref028","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.virol.2012.09.012","article-title":"Anti-viral CD8 T cells and the cytokines that they love","volume":"435","author":"MA Cox","year":"2013","journal-title":"Virology"},{"issue":"5769","key":"ppat.1014150.ref029","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1126\/science.1122927","article-title":"Selective stimulation of T cell subsets with antibody-cytokine immune complexes","volume":"311","author":"O Boyman","year":"2006","journal-title":"Science"},{"issue":"9","key":"ppat.1014150.ref030","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1182\/blood-2008-06-160945","article-title":"IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response","volume":"112","author":"MP Rubinstein","year":"2008","journal-title":"Blood"},{"issue":"8","key":"ppat.1014150.ref031","doi-asserted-by":"crossref","DOI":"10.1016\/j.immuni.2023.06.025","article-title":"Graded expression of the chemokine receptor CX3CR1 marks differentiation states of human and murine T cells and enables cross-species interpretation","volume":"56","author":"AJ Zwijnenburg","year":"2023","journal-title":"Immunity"},{"issue":"7","key":"ppat.1014150.ref032","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nri2580","article-title":"New insights into the regulation of T cells by gamma(c) family cytokines","volume":"9","author":"Y Rochman","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"ppat.1014150.ref033","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-immunol-042617-053352","article-title":"Signaling and function of interleukin-2 in T lymphocytes","volume":"36","author":"SH Ross","year":"2018","journal-title":"Annu Rev Immunol"},{"issue":"729","key":"ppat.1014150.ref034","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.adi1572","article-title":"CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus","volume":"16","author":"F Andreata","year":"2024","journal-title":"Sci Transl Med"},{"issue":"3","key":"ppat.1014150.ref035","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1084\/jem.165.3.650","article-title":"In vivo application of recombinant interleukin 2 in the immunotherapy of established cytomegalovirus infection","volume":"165","author":"MJ Reddehase","year":"1987","journal-title":"J Exp Med"},{"issue":"5","key":"ppat.1014150.ref036","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/80868","article-title":"Interleukin-7 mediates the homeostasis of na\u00efve and memory CD8 T cells in vivo","volume":"1","author":"KS Schluns","year":"2000","journal-title":"Nat Immunol"},{"issue":"5","key":"ppat.1014150.ref037","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S1074-7613(00)80664-0","article-title":"IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation","volume":"9","author":"JP Lodolce","year":"1998","journal-title":"Immunity"},{"issue":"4","key":"ppat.1014150.ref038","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1006993","article-title":"Tissue maintenance of CMV-specific inflationary memory T cells by IL-15","volume":"14","author":"NS Baumann","year":"2018","journal-title":"PLoS Pathog"},{"issue":"7994","key":"ppat.1014150.ref039","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41586-023-06816-9","article-title":"Dictionary of immune responses to cytokines at single-cell resolution","volume":"625","author":"A Cui","year":"2024","journal-title":"Nature"},{"key":"ppat.1014150.ref040","doi-asserted-by":"crossref","first-page":"1117092","DOI":"10.3389\/fimmu.2023.1117092","article-title":"IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation","volume":"14","author":"J Lee","year":"2023","journal-title":"Front Immunol"},{"issue":"4","key":"ppat.1014150.ref041","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1004100","article-title":"Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs","volume":"10","author":"S Ebert","year":"2014","journal-title":"PLoS Pathog"},{"issue":"17","key":"ppat.1014150.ref042","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1016\/j.cell.2021.07.015","article-title":"CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment","volume":"184","author":"M Di Pilato","year":"2021","journal-title":"Cell"},{"issue":"6071","key":"ppat.1014150.ref043","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1126\/science.1215418","article-title":"The alarmin interleukin-33 drives protective antiviral CD8\u207a T cell responses","volume":"335","author":"WV Bonilla","year":"2012","journal-title":"Science"},{"issue":"4","key":"ppat.1014150.ref044","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nri3806","article-title":"Regulation of antiviral T cell responses by type I interferons","volume":"15","author":"J Crouse","year":"2015","journal-title":"Nat Rev Immunol"},{"issue":"8055","key":"ppat.1014150.ref045","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1038\/s41586-024-08510-w","article-title":"IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control","volume":"639","author":"B Br\u00e9art","year":"2025","journal-title":"Nature"},{"issue":"8008","key":"ppat.1014150.ref046","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/s41586-024-07213-6","article-title":"Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency","volume":"628","author":"E Martin","year":"2024","journal-title":"Nature"},{"issue":"7","key":"ppat.1014150.ref047","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0201249","article-title":"IL-27 regulates the number, function and cytotoxic program of antiviral CD4 T cells and promotes cytomegalovirus persistence","volume":"13","author":"EJ Wehrens","year":"2018","journal-title":"PLoS One"},{"key":"ppat.1014150.ref048","article-title":"Reframing IL-27: a central regulator of CD8+ T cell immunity","author":"V Venzin","year":"2025","journal-title":"Trends in Immunology"},{"issue":"84","key":"ppat.1014150.ref049","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.adc9081","article-title":"Activation of regulatory dendritic cells by Mertk coincides with a temporal wave of apoptosis in neonatal lungs","volume":"8","author":"A Silva-Sanchez","year":"2023","journal-title":"Sci Immunol"},{"issue":"4","key":"ppat.1014150.ref050","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1128\/jvi.66.4.1977-1984.1992","article-title":"Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands","volume":"66","author":"P Lucin","year":"1992","journal-title":"J Virol"},{"issue":"5","key":"ppat.1014150.ref051","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1084\/jem.179.5.1713","article-title":"Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus","volume":"179","author":"S Jonji\u0107","year":"1994","journal-title":"J Exp Med"},{"issue":"10","key":"ppat.1014150.ref052","doi-asserted-by":"crossref","first-page":"3102","DOI":"10.1128\/jvi.61.10.3102-3108.1987","article-title":"CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity","volume":"61","author":"MJ Reddehase","year":"1987","journal-title":"J Virol"},{"issue":"6491","key":"ppat.1014150.ref053","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1126\/science.aaz9330","article-title":"Prenatal development of human immunity","volume":"368","author":"J-E Park","year":"2020","journal-title":"Science"},{"issue":"2","key":"ppat.1014150.ref054","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jcv.2005.09.015","article-title":"Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome","volume":"35","author":"RF Pass","year":"2006","journal-title":"J Clin Virol"},{"issue":"14","key":"ppat.1014150.ref055","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1001\/jama.1986.03380140074025","article-title":"Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome","volume":"256","author":"S Stagno","year":"1986","journal-title":"JAMA"},{"issue":"2","key":"ppat.1014150.ref056","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3109\/inf.1983.15.issue-2.01","article-title":"Congenital cytomegalovirus infection: on the relation between type and time of maternal infection and infant\u2019s symptoms","volume":"15","author":"K Ahlfors","year":"1983","journal-title":"Scand J Infect Dis"},{"issue":"9","key":"ppat.1014150.ref057","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1084\/jem.194.9.1385","article-title":"Most alpha\/beta T cell receptor diversity is due to terminal deoxynucleotidyl transferase","volume":"194","author":"JP Cabaniols","year":"2001","journal-title":"J Exp Med"},{"issue":"22","key":"ppat.1014150.ref058","doi-asserted-by":"crossref","first-page":"11011","DOI":"10.1073\/pnas.89.22.11011","article-title":"Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny","volume":"89","author":"M Bogue","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"ppat.1014150.ref059","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0014-5793(97)00313-X","article-title":"\u201cGreen mice\u201d as a source of ubiquitous green cells","volume":"407","author":"M Okabe","year":"1997","journal-title":"FEBS Lett"},{"key":"ppat.1014150.ref060","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1472-6750-2-11","article-title":"Embryonic stem cells and mice expressing different GFP variants for multiple non-invasive reporter usage within a single animal","volume":"2","author":"A-K Hadjantonakis","year":"2002","journal-title":"BMC Biotechnol"},{"issue":"5","key":"ppat.1014150.ref061","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","article-title":"RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement","volume":"68","author":"Y Shinkai","year":"1992","journal-title":"Cell"},{"issue":"3","key":"ppat.1014150.ref062","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/1074-7613(95)90047-0","article-title":"Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain","volume":"2","author":"X Cao","year":"1995","journal-title":"Immunity"},{"issue":"1","key":"ppat.1014150.ref063","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1046\/j.1440-1711.1998.00709.x","article-title":"Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements","volume":"76","author":"MJ Barnden","year":"1998","journal-title":"Immunol Cell Biol"},{"issue":"1","key":"ppat.1014150.ref064","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0092-8674(94)90169-4","article-title":"T cell receptor antagonist peptides induce positive selection","volume":"76","author":"KA Hogquist","year":"1994","journal-title":"Cell"},{"issue":"3","key":"ppat.1014150.ref065","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1128\/JVI.02087-09","article-title":"Immune evasion proteins of murine cytomegalovirus preferentially affect cell surface display of recently generated peptide presentation complexes","volume":"84","author":"NAW Lemmermann","year":"2010","journal-title":"J Virol"},{"key":"ppat.1014150.ref066","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/978-1-60761-652-8_30","article-title":"En passant mutagenesis: a two step markerless red recombination system","volume":"634","author":"BK Tischer","year":"2010","journal-title":"Methods Mol Biol"},{"key":"ppat.1014150.ref067","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1101\/gad.5.12b.2375","article-title":"p53 alteration is a common event in the spontaneous immortalization of primary BALB\/c murine embryo fibroblasts","volume":"5","author":"DM Harvey","year":"1991","journal-title":"Genes Dev"},{"issue":"13","key":"ppat.1014150.ref068","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Y Hao","year":"2021","journal-title":"Cell"},{"issue":"1","key":"ppat.1014150.ref069","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s13059-019-1874-1","article-title":"Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression","volume":"20","author":"C Hafemeister","year":"2019","journal-title":"Genome Biol"},{"issue":"9","key":"ppat.1014150.ref070","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abe3348","article-title":"Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer","volume":"7","author":"A Cachot","year":"2021","journal-title":"Sci Adv"},{"issue":"2","key":"ppat.1014150.ref071","article-title":"Single-cell transcriptomics reveals a low CD8+ T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma","volume":"10","author":"Y-L Peng","year":"2022","journal-title":"J Immunother Cancer"},{"key":"ppat.1014150.ref072","volume-title":"R: A language and environment for statistical computing","author":"R Development Core Team","year":"2021"},{"key":"ppat.1014150.ref073","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"H Wickham","year":"2016"},{"issue":"12","key":"ppat.1014150.ref074","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"key":"ppat.1014150.ref075","volume-title":"fmsb: Functions for Medical Statistics Book with Some Demographic Data","author":"M Nakazawa","year":"2023","edition":"0"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1014150","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T18:02:54Z","timestamp":1777485774000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014150"}},"subtitle":[],"editor":[{"given":"Eain A","family":"Murphy","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":75,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1014150","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]}}}