{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:43:39Z","timestamp":1790642619546,"version":"4.1.0"},"reference-count":103,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T00:00:00Z","timestamp":1585008000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T00:00:00Z","timestamp":1585008000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T00:00:00Z","timestamp":1585008000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BBS\/E\/B\/000C0407"],"award-info":[{"award-number":["BBS\/E\/B\/000C0407"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BBS\/E\/B\/000C0408"],"award-info":[{"award-number":["BBS\/E\/B\/000C0408"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["637801"],"award-info":[{"award-number":["637801"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["675395"],"award-info":[{"award-number":["675395"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.<\/jats:p>","DOI":"10.7554\/elife.52473","type":"journal-article","created":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T20:00:19Z","timestamp":1584993619000},"source":"Crossref","is-referenced-by-count":73,"title":["Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8434-8271","authenticated-orcid":true,"given":"Marisa","family":"Stebegg","sequence":"first","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Bignon","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danika Lea","family":"Hill","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0533-1629","authenticated-orcid":true,"given":"Alyssa","family":"Silva-Cayetano","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5601-598X","authenticated-orcid":true,"given":"Christel","family":"Krueger","sequence":"additional","affiliation":[{"name":"Epigenetics Programme, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ine","family":"Vanderleyden","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Innocentin","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Boon","sequence":"additional","affiliation":[{"name":"Bioceros BV, Utrecht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine and Clinical and Translational Science Institute, University of Rochester Medical Center, Rochester, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S","family":"Zand","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine and Clinical and Translational Science Institute, University of Rochester Medical Center, Rochester, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Dooley","sequence":"additional","affiliation":[{"name":"Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Clark","sequence":"additional","affiliation":[{"name":"Biological Chemistry, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Liston","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-4593","authenticated-orcid":true,"given":"Edward","family":"Carr","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"},{"name":"Department of Medicine, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6047-1996","authenticated-orcid":true,"given":"Michelle A","family":"Linterman","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,3,24]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s11357-011-9371-9","article-title":"Mechanistic insights into the impairment of memory B cells and antibody production in the elderly","volume":"35","author":"Aberle","year":"2013","journal-title":"Age"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"6912","DOI":"10.4049\/jimmunol.178.11.6912","article-title":"Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-Kinase-Signaling pathway","volume":"178","author":"Agrawal","year":"2007","journal-title":"The Journal of Immunology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1159\/000350536","article-title":"Mechanisms and implications of Age-Associated impaired innate interferon secretion by dendritic cells: a Mini-Review","volume":"59","author":"Agrawal","year":"2013","journal-title":"Gerontology"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00896","article-title":"Role of dendritic cells in inflammation and loss of tolerance in the elderly","volume":"8","author":"Agrawal","year":"2017","journal-title":"Frontiers in Immunology"},{"key":"bib5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00778","article-title":"Sources of type I interferons in infectious immunity: plasmacytoid dendritic cells not always in the driver's Seat","volume":"10","author":"Ali","year":"2019","journal-title":"Frontiers in Immunology"},{"key":"bib6","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf9194","article-title":"Influenza vaccines differentially regulate the interferon response in human dendritic cell subsets","volume":"9","author":"Athale","year":"2017","journal-title":"Science Translational Medicine"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"5975","DOI":"10.4049\/jimmunol.171.11.5975","article-title":"Altered regulation of fc\u03b3rii on aged follicular dendritic cells correlates with immunoreceptor Tyrosine-Based inhibition motif signaling in B cells and reduced germinal center formation","volume":"171","author":"Aydar","year":"2003","journal-title":"The Journal of Immunology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.immuni.2018.02.015","article-title":"Sensing microbial viability through bacterial RNA augments T follicular helper cell and antibody responses","volume":"48","author":"Barbet","year":"2018","journal-title":"Immunity"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1046\/j.1440-1711.1998.00709.x","article-title":"Defective TCR expression in transgenic mice constructed using cDNA-based \u03b1- and \u03b2-chain genes under the control of heterologous regulatory elements","volume":"76","author":"Barnden","year":"1998","journal-title":"Immunology and Cell Biology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"3607","DOI":"10.4049\/jimmunol.1301284","article-title":"B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation","volume":"192","author":"Barnett","year":"2014","journal-title":"The Journal of Immunology"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"2895","DOI":"10.1084\/jem.20100064","article-title":"IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells","volume":"207","author":"Batten","year":"2010","journal-title":"The Journal of Experimental Medicine"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.immuni.2012.11.020","article-title":"Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype","volume":"38","author":"Baumjohann","year":"2013","journal-title":"Immunity"},{"key":"bib13","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005191","article-title":"Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination","volume":"5","author":"Bentebibel","year":"2013","journal-title":"Science Translational Medicine"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1128\/AAC.43.4.856","article-title":"The immune response modifier imiquimod requires STAT-1 for induction of interferon, Interferon-Stimulated genes, and Interleukin-6","volume":"43","author":"Bottrel","year":"1999","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"2819","DOI":"10.4049\/jimmunol.1601119","article-title":"IL-6 production by TLR-Activated APC broadly enhances aged cognate CD4 helper and B cell antibody responses in vivo","volume":"198","author":"Brahmakshatriya","year":"2017","journal-title":"The Journal of Immunology"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.celrep.2019.12.016","article-title":"CD4+ T follicular helper cells in human tonsils and blood are clonally convergent but divergent from Non-Tfh CD4+ cells","volume":"30","author":"Brenna","year":"2020","journal-title":"Cell Reports"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1084\/jem.20062648","article-title":"Notch\u2013RBP-J signaling controls the homeostasis of CD8\u2212 dendritic cells in the spleen","volume":"204","author":"Caton","year":"2007","journal-title":"The Journal of Experimental Medicine"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1002\/emmm.201403841","article-title":"Monocyte-derived dendritic cells promote T follicular helper cell differentiation","volume":"6","author":"Chakarov","year":"2014","journal-title":"\u00a0EMBO Molecular Medicine. Wiley-Blackwell"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1128\/aac.32.5.678","article-title":"\u2018Efficacy of S26308 against guinea pig cytomegalovirus infection\u2019, Antimicrobial Agents and Chemotherapy","volume":"32","author":"Chen","year":"1988","journal-title":"American Society for Microbiology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.immuni.2009.07.005","article-title":"Type I interferon signaling in dendritic cells stimulates the development of Lymph-Node-Resident T follicular helper cells","volume":"31","author":"Cucak","year":"2009","journal-title":"Immunity"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"5187","DOI":"10.4049\/jimmunol.1401938","article-title":"T follicular helper, but not Th1, cell differentiation in the absence of conventional dendritic cells","volume":"194","author":"Dahlgren","year":"2015","journal-title":"The Journal of Immunology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1084\/jem.20181216","article-title":"Type I interferon induces CXCL13 to support ectopic germinal center formation","volume":"216","author":"Denton","year":"2019","journal-title":"Journal of Experimental Medicine"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1084\/jem.20181994","article-title":"Human lymphoid organ cDC2 and macrophages play complementary roles in T follicular helper responses","volume":"216","author":"Durand","year":"2019","journal-title":"The Journal of Experimental Medicine"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1084\/jem.20041395","article-title":"Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses","volume":"200","author":"Eaton","year":"2004","journal-title":"The Journal of Experimental Medicine"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1182\/blood-2008-04-154682","article-title":"Interleukin-6\/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities","volume":"113","author":"Eddahri","year":"2009","journal-title":"Blood"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00299","article-title":"Integrative genomic analysis of the human immune response to influenza vaccination","volume":"2","author":"Franco","year":"2013","journal-title":"eLife"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.vaccine.2004.06.036","article-title":"Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch","volume":"23","author":"Frech","year":"2005","journal-title":"Vaccine"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.4049\/jimmunol.166.5.3151","article-title":"Single-cell analyses reveal two defects in peptide-specific activation of naive T cells from aged mice","volume":"166","author":"Garcia","year":"2001","journal-title":"The Journal of Immunology"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/bioinformatics\/btg405","article-title":"Affy--analysis of affymetrix GeneChip data at the probe level","volume":"20","author":"Gautier","year":"2004","journal-title":"Bioinformatics"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nature13300","article-title":"Clonal selection in the germinal centre by regulated proliferation and hypermutation","volume":"509","author":"Gitlin","year":"2014","journal-title":"Nature"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.4049\/jimmunol.1100853","article-title":"Cutting edge: dendritic Cell-Restricted antigen presentation initiates the follicular helper T cell program but Cannot complete ultimate effector differentiation","volume":"187","author":"Goenka","year":"2011","journal-title":"The Journal of Immunology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1084\/jem.20130505","article-title":"Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation","volume":"211","author":"Goenka","year":"2014","journal-title":"The Journal of Experimental Medicine"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/j.vaccine.2005.08.105","article-title":"Antibody response to influenza vaccination in the elderly: a quantitative review","volume":"24","author":"Goodwin","year":"2006","journal-title":"Vaccine"},{"key":"bib34","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1001\/jama.1994.03520210045030","article-title":"The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial","volume":"272","author":"Govaert","year":"1994","journal-title":"Jama"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6074","article-title":"Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production","volume":"5","author":"Gringhuis","year":"2014","journal-title":"Nature Communications"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.immuni.2016.08.015","article-title":"Unsupervised High-Dimensional analysis aligns dendritic cells across tissues and species","volume":"45","author":"Guilliams","year":"2016","journal-title":"Immunity"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1042\/CS20171157","article-title":"T follicular helper cell development and functionality in immune ageing","volume":"132","author":"Gustafson","year":"2018","journal-title":"Clinical Science"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"375","DOI":"10.4049\/jimmunol.1601143","article-title":"Autocrine type I IFN signaling in dendritic cells stimulated with fungal \u03b2-Glucans or lipopolysaccharide promotes CD8 T cell activation","volume":"198","author":"Hassanzadeh-Kiabi","year":"2017","journal-title":"The Journal of Immunology"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1084\/jem.20161794","article-title":"Vaccination establishes clonal relatives of germinal center T cells in the blood of humans","volume":"214","author":"Heit","year":"2017","journal-title":"The Journal of Experimental Medicine"},{"key":"bib40","doi-asserted-by":"publisher","DOI":"10.1038\/srep02327","article-title":"High-Resolution temporal response patterns to influenza vaccine reveal a distinct human plasma cell gene signature","volume":"3","author":"Henn","year":"2013","journal-title":"Scientific Reports"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.1158\/1078-0432.CCR-10-1114","article-title":"\u2018Direct effects of type I interferons on cells of the immune system\u2019, Clinical Cancer Research","author":"Hervas-Stubbs","year":"2011","journal-title":"American Association for Cancer Research"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1084\/jem.20190301","article-title":"The adjuvant GLA-SE promotes human tfh cell expansion and emergence of public tcr\u03b2 clonotypes","volume":"216","author":"Hill","year":"2019","journal-title":"The Journal of Experimental Medicine"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.it.2015.01.004","article-title":"Interferons and viruses: an evolutionary arms race of molecular interactions","volume":"36","author":"Hoffmann","year":"2015","journal-title":"Trends in Immunology"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1093\/cid\/ciu582","article-title":"Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial","volume":"59","author":"Hung","year":"2014","journal-title":"Clinical Infectious Diseases"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/S1473-3099(15)00354-0","article-title":"Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b\/3 trial","volume":"16","author":"Hung","year":"2016","journal-title":"The Lancet Infectious Diseases"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nature Methods"},{"key":"bib48","first-page":"312","article-title":"Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing","volume":"68","author":"Kosco","year":"1989","journal-title":"Immunology"},{"key":"bib49","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aam9169","article-title":"Migratory CD11b + conventional dendritic cells induce T follicular helper cell\u2013dependent antibody responses","volume":"2","author":"Krishnaswamy","year":"2017","journal-title":"Science Immunology"},{"key":"bib50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02169","article-title":"Determination of T follicular helper cell fate by dendritic cells","volume":"9","author":"Krishnaswamy","year":"2018","journal-title":"Frontiers in Immunology"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.4049\/jimmunol.176.4.2074","article-title":"Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN","volume":"176","author":"Le Bon","year":"2006","journal-title":"The Journal of Immunology"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1111\/j.1474-9726.2012.00836.x","article-title":"The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice","volume":"11","author":"Lefebvre","year":"2012","journal-title":"Aging Cell"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1016\/j.jid.2017.04.016","article-title":"Critical role for Skin-Derived migratory DCs and Langerhans cells in TFH and GC responses after intradermal immunization","volume":"137","author":"Levin","year":"2017","journal-title":"Journal of Investigative Dermatology"},{"key":"bib54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02370","article-title":"Co-stimulation with TLR7 agonist imiquimod and inactivated influenza virus particles promotes mouse B cell activation, differentiation, and accelerated antigen specific antibody production","volume":"9","author":"Li","year":"2018","journal-title":"Frontiers in Immunology"},{"key":"bib55","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz114","article-title":"The R package rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The molecular signatures database hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Systems"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1084\/jem.20081886","article-title":"Follicular helper T cells are required for systemic autoimmunity","volume":"206","author":"Linterman","year":"2009","journal-title":"The Journal of Experimental Medicine"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/icb.2013.77","article-title":"How T follicular helper cells and the germinal centre response change with age","volume":"92","author":"Linterman","year":"2014","journal-title":"Immunology and Cell Biology"},{"key":"bib59","doi-asserted-by":"publisher","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":"Love","year":"2014","journal-title":"Genome Biology"},{"key":"bib60","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.4049\/jimmunol.161.4.1947","article-title":"\u2018Type I IFNs enhance the terminal differentiation of dendritic cells.\u2019","volume":"161","author":"Luft","year":"1998","journal-title":"Journal of Immunology"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1034\/j.1600-065X.2003.00058.x","article-title":"Extrafollicular antibody responses","volume":"194","author":"MacLennan","year":"2003","journal-title":"Immunological Reviews"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"10338","DOI":"10.1073\/pnas.96.18.10338","article-title":"Mice lacking all conventional MHC class II genes","volume":"96","author":"Madsen","year":"1999","journal-title":"PNAS"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1177\/0023677213516312","article-title":"FELASA recommendations for the health monitoring of mouse, rat, hamster, guinea pig and rabbit colonies in breeding and experimental units","volume":"48","author":"M\u00e4hler","year":"2014","journal-title":"Laboratory Animals"},{"key":"bib64","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013984","article-title":"Enrichment map: a Network-Based method for Gene-Set enrichment visualization and interpretation","volume":"5","author":"Merico","year":"2010","journal-title":"PLOS ONE"},{"key":"bib65","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-1-3","article-title":"Imiquimod for the treatment of genital warts: a quantitative systematic review","volume":"1","author":"Moore","year":"2001","journal-title":"BMC Infectious Diseases"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"7977","DOI":"10.4049\/jimmunol.181.11.7977","article-title":"Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen","volume":"181","author":"Moretto","year":"2008","journal-title":"The Journal of Immunology"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/ni.2067","article-title":"Systems biology of vaccination for seasonal influenza in humans","volume":"12","author":"Nakaya","year":"2011","journal-title":"Nature Immunology"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1016\/j.immuni.2015.11.012","article-title":"Systems analysis of immunity to influenza vaccination across multiple years and in diverse populations reveals shared molecular signatures","volume":"43","author":"Nakaya","year":"2015","journal-title":"Immunity"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.4049\/jimmunol.1300675","article-title":"Type I IFN induces binding of STAT1 to Bcl6: divergent roles of STAT family transcription factors in the T follicular helper cell genetic program","volume":"192","author":"Nakayamada","year":"2014","journal-title":"The Journal of Immunology"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1002\/eji.200636432","article-title":"Breakpoints in Immunoregulation required for Th1 cells to induce diabetes","volume":"36","author":"Neighbors","year":"2006","journal-title":"European Journal of Immunology"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/s41590-017-0006-x","article-title":"The twilight of immunity: emerging concepts in aging of the immune system","volume":"19","author":"Nikolich-\u017dugich","year":"2018","journal-title":"Nature Immunology"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.4049\/jimmunol.0901022","article-title":"Age-Associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response","volume":"184","author":"Panda","year":"2010","journal-title":"The Journal of Immunology"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.4049\/jimmunol.1001311","article-title":"Abatacept limits breach of Self-Tolerance in a murine model of arthritis via effects on the generation of T follicular helper cells","volume":"185","author":"Platt","year":"2010","journal-title":"The Journal of Immunology"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"375","DOI":"10.4049\/jimmunol.169.1.375","article-title":"Type I IFN as a natural adjuvant for a protective immune response: lessons from the influenza vaccine model","volume":"169","author":"Proietti","year":"2002","journal-title":"The Journal of Immunology"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1002\/jlb.55.2.234","article-title":"Cytokine induction in mice by the immunomodulator imiquimod","volume":"55","author":"Reiter","year":"1994","journal-title":"Journal of Leukocyte Biology"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/0264-410X(93)90311-K","article-title":"Improvement of the immunoglobulin subclass response to influenza vaccine in elderly nursing-home residents by the use of high-dose vaccines","volume":"11","author":"Remarque","year":"1993","journal-title":"Vaccine"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/nbt.2931","article-title":"Normalization of RNA-seq data using factor analysis of control genes or samples","volume":"32","author":"Risso","year":"2014","journal-title":"Nature Biotechnology"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"3884","DOI":"10.4049\/jimmunol.1600883","article-title":"Water-in-Oil\u2013Only Adjuvants Selectively Promote T Follicular Helper Cell Polarization through a Type I IFN and IL-6\u2013Dependent Pathway","volume":"197","author":"Riteau","year":"2016","journal-title":"The Journal of Immunology"},{"key":"bib79","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/978-1-60761-585-9_12","article-title":"Tracking dendritic cells in vivo","volume":"626","author":"Rush","year":"2010","journal-title":"Methods in Molecular Biology"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.celrep.2015.06.015","article-title":"Defective TFH cell function and increased TFR cells contribute to defective antibody production in aging","volume":"12","author":"Sage","year":"2015","journal-title":"Cell Reports"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"3109","DOI":"10.1172\/JCI57834","article-title":"Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies","volume":"121","author":"Sasaki","year":"2011","journal-title":"Journal of Clinical Investigation"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1046\/j.0366-077X.2003.05628.x","article-title":"Imiquimod: modes of action","volume":"149","author":"Sauder","year":"2003","journal-title":"British Journal of Dermatology"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/j.1365-2133.2007.08265.x","article-title":"Imiquimod: mode of action","volume":"157","author":"Sch\u00f6n","year":"2007","journal-title":"British Journal of Dermatology"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature10163","article-title":"A conditional knockout resource for the genome-wide study of mouse gene function","volume":"474","author":"Skarnes","year":"2011","journal-title":"Nature"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s11357-010-9191-3","article-title":"Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity","volume":"33","author":"Sridharan","year":"2011","journal-title":"Age"},{"key":"bib86","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02469","article-title":"Regulation of the germinal center response","volume":"9","author":"Stebegg","year":"2018","journal-title":"Frontiers in Immunology"},{"key":"bib87","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10430-7","article-title":"Heterochronic faecal transplantation boosts gut germinal centres in aged mice","volume":"10","author":"Stebegg","year":"2019","journal-title":"Nature Communications"},{"key":"bib88","doi-asserted-by":"publisher","first-page":"6747","DOI":"10.4049\/jimmunol.181.10.6747","article-title":"Aging impairs IFN regulatory factor 7 Up-Regulation in plasmacytoid dendritic cells during TLR9 activation","volume":"181","author":"Stout-Delgado","year":"2008","journal-title":"The Journal of Immunology"},{"key":"bib89","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"PNAS"},{"key":"bib90","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.coviro.2011.10.026","article-title":"Type I interferons: diversity of sources, production pathways and effects on immune responses","volume":"1","author":"Swiecki","year":"2011","journal-title":"Current Opinion in Virology"},{"key":"bib91","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1002\/ar.1092270411","article-title":"Kinetics of germinal center development in lymph nodes of young and aging immune mice","volume":"227","author":"Szakal","year":"1990","journal-title":"The Anatomical Record"},{"key":"bib92","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1111\/imm.12727","article-title":"Structural and functional changes to lymph nodes in ageing mice","volume":"151","author":"Turner","year":"2017","journal-title":"Immunology"},{"key":"bib93","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1002\/eji.1830270613","article-title":"Age-related impaired affinity maturation and differential D-JH gene usage in human VH6-expressing B lymphocytes from healthy individuals","volume":"27","author":"van Dijk-H\u00e4rd","year":"1997","journal-title":"European Journal of Immunology"},{"key":"bib94","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.cell.2010.10.032","article-title":"Germinal center dynamics revealed by multiphoton microscopy with\u00a0a Photoactivatable Fluorescent Reporter","volume":"143","author":"Victora","year":"2010","journal-title":"Cell"},{"key":"bib95","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1146\/annurev-immunol-041015-055605","article-title":"Follicular helper T cells","volume":"34","author":"Vinuesa","year":"2016","journal-title":"Annual Review of Immunology"},{"key":"bib96","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2566","article-title":"Aldara activates TLR7-independent immune defence","volume":"4","author":"Walter","year":"2013","journal-title":"Nature Communications"},{"key":"bib97","doi-asserted-by":"publisher","first-page":"2497","DOI":"10.1084\/jem.20111449","article-title":"Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers","volume":"208","author":"Wang","year":"2011","journal-title":"The Journal of Experimental Medicine"},{"key":"bib98","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1073\/pnas.1414576112","article-title":"CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement","volume":"112","author":"Wang","year":"2015","journal-title":"PNAS"},{"key":"bib99","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129858","article-title":"Multi-Dimensional measurement of Antibody-Mediated heterosubtypic immunity to influenza","volume":"10","author":"Wang","year":"2015","journal-title":"PLOS ONE"},{"key":"bib100","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1111\/imm.12778","article-title":"Signals that drive T follicular helper cell formation","volume":"152","author":"Webb","year":"2017","journal-title":"Immunology"},{"key":"bib101","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1084\/jem.20132327","article-title":"Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine","volume":"211","author":"Woodruff","year":"2014","journal-title":"The Journal of Experimental Medicine"},{"key":"bib102","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1084\/jem.183.3.959","article-title":"Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice","volume":"183","author":"Yang","year":"1996","journal-title":"The Journal of Experimental Medicine"},{"key":"bib103","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1016\/j.jaci.2015.04.001","article-title":"Skin dendritic cells induce follicular helper T cells and protective humoral immune responses","volume":"136","author":"Yao","year":"2015","journal-title":"Journal of Allergy and Clinical Immunology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/52473\/elife-52473-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/52473\/elife-52473-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/52473","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:59:01Z","timestamp":1697057941000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/52473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,24]]},"references-count":103,"alternative-id":["10.7554\/eLife.52473"],"URL":"https:\/\/doi.org\/10.7554\/elife.52473","archive":["CLOCKSS"],"relation":{"references":[{"id-type":"accession","id":"SRP020492","asserted-by":"subject"},{"id-type":"accession","id":"GSE74813","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"accession","id":"GSE133148","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.52473.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.52473.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,24]]},"article-number":"e52473"}}