{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:17:34Z","timestamp":1790731054470,"version":"4.1.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,5,27]],"date-time":"2016-05-27T00:00:00Z","timestamp":1464307200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,5,27]],"date-time":"2016-05-27T00:00:00Z","timestamp":1464307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.\n                  <\/jats:p>","DOI":"10.1038\/srep26494","type":"journal-article","created":{"date-parts":[[2016,5,27]],"date-time":"2016-05-27T05:25:23Z","timestamp":1464326723000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":172,"title":["ICOS+PD-1+CXCR3+ T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination"],"prefix":"10.1038","volume":"6","author":[{"given":"Salah-Eddine","family":"Bentebibel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surender","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvathi","family":"Kurup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerlinde","family":"Obermoser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Karolina","family":"Palucka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy A.","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Garcia-Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Golding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,27]]},"reference":[{"key":"BFsrep26494_CR1","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1056\/NEJM199409223311206","volume":"331","author":"KL Nichol","year":"1994","unstructured":"Nichol, K. L., Margolis, K. L., Wuorenma, J. & Von Sternberg, T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. New England Journal of Medicine 331, 778\u2013784 (1994).","journal-title":"New England Journal of Medicine"},{"key":"BFsrep26494_CR2","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/S1473-3099(11)70295-X","volume":"12","author":"MT Osterholm","year":"2012","unstructured":"Osterholm, M. T., Kelley, N. S., Sommer, A. & Belongia, E. A. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. The Lancet infectious diseases 12, 36\u201344 (2012).","journal-title":"The Lancet infectious diseases"},{"key":"BFsrep26494_CR3","first-page":"1","volume":"59","author":"AE Fiore","year":"2010","unstructured":"Fiore, A. E. et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR . Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports\/Centers for Disease Control 59, 1\u201362 (2010).","journal-title":"Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports\/Centers for Disease Control"},{"key":"BFsrep26494_CR4","doi-asserted-by":"publisher","first-page":"176ra132","DOI":"10.1126\/scitranslmed.3005191","volume":"5","author":"SE Bentebibel","year":"2013","unstructured":"Bentebibel, S. E. et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Science Translational Medicine 5, 176ra132 (2013).","journal-title":"Science Translational Medicine"},{"key":"BFsrep26494_CR5","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.it.2014.06.002","volume":"35","author":"N Schmitt","year":"2014","unstructured":"Schmitt, N., Bentebibel, S. E. & Ueno, H. Phenotype and functions of memory Tfh cells in human blood. Trends Immunol 35, 436\u2013442 (2014).","journal-title":"Trends Immunol"},{"key":"BFsrep26494_CR6","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/ni.3054","volume":"16","author":"H Ueno","year":"2015","unstructured":"Ueno, H., Banchereau, J. & Vinuesa, C. G. Pathophysiology of T follicular helper cells in humans and mice. Nature immunology 16, 142\u2013152 (2015).","journal-title":"Nature immunology"},{"key":"BFsrep26494_CR7","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.immuni.2010.12.012","volume":"34","author":"R Morita","year":"2011","unstructured":"Morita, R. et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108\u2013121 (2011).","journal-title":"Immunity"},{"key":"BFsrep26494_CR8","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.immuni.2013.08.031","volume":"39","author":"M Locci","year":"2013","unstructured":"Locci, M. et al. Human Circulating PD-1(+)CXCR3(\u2212)CXCR5(+) Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses. Immunity 39, 758\u2013769 (2013).","journal-title":"Immunity"},{"key":"BFsrep26494_CR9","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.celrep.2015.09.004","volume":"13","author":"N Obeng-Adjei","year":"2015","unstructured":"Obeng-Adjei, N. et al. Circulating Th1-Cell-type Tfh Cells that Exhibit Impaired B Cell Help Are Preferentially Activated during Acute Malaria in Children. Cell reports 13, 425\u2013439 (2015).","journal-title":"Cell reports"},{"key":"BFsrep26494_CR10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1034\/j.1600-065X.2003.00058.x","volume":"194","author":"IC MacLennan","year":"2003","unstructured":"MacLennan, I. C. et al. Extrafollicular antibody responses. Immunological reviews 194, 8\u201318 (2003).","journal-title":"Immunological reviews"},{"key":"BFsrep26494_CR11","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1146\/annurev-immunol-020711-075032","volume":"30","author":"GD Victora","year":"2012","unstructured":"Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annual review of immunology 30, 429\u2013457 (2012).","journal-title":"Annual review of immunology"},{"key":"BFsrep26494_CR12","doi-asserted-by":"publisher","first-page":"e11548","DOI":"10.1371\/journal.pone.0011548","volume":"5","author":"S Khurana","year":"2010","unstructured":"Khurana, S. et al. Properly folded bacterially expressed H1N1 hemagglutinin globular head and ectodomain vaccines protect ferrets against H1N1 pandemic influenza virus. Plos One 5, e11548 (2010).","journal-title":"Plos One"},{"key":"BFsrep26494_CR13","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/nm1293","volume":"11","author":"PK Chattopadhyay","year":"2005","unstructured":"Chattopadhyay, P. K., Yu, J. & Roederer, M. A live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles. Nature medicine 11, 1113\u20131117 (2005).","journal-title":"Nature medicine"},{"key":"BFsrep26494_CR14","doi-asserted-by":"publisher","first-page":"3582","DOI":"10.1016\/j.vaccine.2010.02.088","volume":"28","author":"JL Halliley","year":"2010","unstructured":"Halliley, J. L. et al. Peak frequencies of circulating human influenza-specific antibody secreting cells correlate with serum antibody response after immunization. Vaccine 28, 3582\u20133587 (2010).","journal-title":"Vaccine"},{"key":"BFsrep26494_CR15","doi-asserted-by":"publisher","first-page":"9047","DOI":"10.1073\/pnas.1118979109","volume":"109","author":"GM Li","year":"2012","unstructured":"Li, G. M. et al. Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proceedings of the National Academy of Sciences 109, 9047\u20139052 (2012).","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"BFsrep26494_CR16","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/nature06890","volume":"453","author":"J Wrammert","year":"2008","unstructured":"Wrammert, J. et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667\u2013671 (2008).","journal-title":"Nature"},{"key":"BFsrep26494_CR17","doi-asserted-by":"publisher","first-page":"171ra119","DOI":"10.1126\/scitranslmed.3004794","volume":"5","author":"N Jiang","year":"2013","unstructured":"Jiang, N. et al. Lineage structure of the human antibody repertoire in response to influenza vaccination. Science Translational Medicine 5, 171ra119 (2013).","journal-title":"Science Translational Medicine"},{"key":"BFsrep26494_CR18","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1093\/infdis\/jir791","volume":"205","author":"S Khurana","year":"2012","unstructured":"Khurana, S., Verma, N., Talaat, K. R., Karron, R. A. & Golding, H. Immune response following H1N1pdm09 vaccination: differences in antibody repertoire and avidity in young adults and elderly populations stratified by age and gender. The Journal of infectious diseases 205, 610\u2013620 (2012).","journal-title":"The Journal of infectious diseases"},{"key":"BFsrep26494_CR19","doi-asserted-by":"publisher","first-page":"198ra107","DOI":"10.1126\/scitranslmed.3006637","volume":"5","author":"MS Miller","year":"2013","unstructured":"Miller, M. S. et al. Neutralizing antibodies against previously encountered influenza virus strains increase over time: a longitudinal analysis. Science Translational Medicine 5, 198ra107 (2013).","journal-title":"Science Translational Medicine"},{"key":"BFsrep26494_CR20","doi-asserted-by":"publisher","first-page":"e2975","DOI":"10.1371\/journal.pone.0002975","volume":"3","author":"S Sasaki","year":"2008","unstructured":"Sasaki, S. et al. Influence of prior influenza vaccination on antibody and B-cell responses. Plos One 3, e2975 (2008).","journal-title":"Plos One"},{"key":"BFsrep26494_CR21","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.cell.2010.10.032","volume":"143","author":"GD Victora","year":"2010","unstructured":"Victora, G. D. et al. Germinal Center Dynamics Revealed by Multiphoton Microscopy with a Photoactivatable Fluorescent Reporter. Cell 143, 592\u2013605 (2010).","journal-title":"Cell"},{"key":"BFsrep26494_CR22","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1084\/jem.20060087","volume":"203","author":"D Paus","year":"2006","unstructured":"Paus, D. et al. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. The Journal of experimental medicine 203, 1081\u20131091 (2006).","journal-title":"The Journal of experimental medicine"},{"key":"BFsrep26494_CR23","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.immuni.2013.09.007","volume":"39","author":"J He","year":"2013","unstructured":"He, J. et al. Circulating Precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T Cells Indicate Tfh Cell Activity and Promote Antibody Responses upon Antigen Reexposure. Immunity 39, 770\u2013781 (2013).","journal-title":"Immunity"},{"key":"BFsrep26494_CR24","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/icb.2013.68","volume":"92","author":"LM Tsai","year":"2014","unstructured":"Tsai, L. M. & Yu, D. Follicular helper T-cell memory: establishing new frontiers during antibody response. Immunology and cell biology 92, 57\u201363 (2014).","journal-title":"Immunology and cell biology"},{"key":"BFsrep26494_CR25","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.coviro.2013.07.007","volume":"3","author":"F Krammer","year":"2013","unstructured":"Krammer, F. & Palese, P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Current opinion in virology 3, 521\u2013530 (2013).","journal-title":"Current opinion in virology"},{"key":"BFsrep26494_CR26","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/978-1-4939-2498-1_16","volume":"1291","author":"SE Bentebibel","year":"2015","unstructured":"Bentebibel, S. E., Jacquemin, C., Schmitt, N. & Ueno, H. Analysis of human blood memory T follicular helper subsets. Methods Mol Biol 1291, 187\u2013197 (2015).","journal-title":"Methods Mol Biol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep26494.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep26494","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep26494.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T23:29:16Z","timestamp":1672874956000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep26494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,27]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,5,31]]}},"alternative-id":["BFsrep26494"],"URL":"https:\/\/doi.org\/10.1038\/srep26494","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,27]]},"assertion":[{"value":"23 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"26494"}}