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We show that Tfr cells promote antigen-specific germinal center B cell responses upon influenza virus infection. Following viral challenge, we found that Tfr cells are necessary for robust generation of virus-specific, long-lived plasma cells, antibody production against both hemagglutinin (HA) and neuraminidase (NA), the two major influenza virus glycoproteins, and appropriate regulation of the BCR repertoire. To further investigate the functional relevance of Tfr cells during viral challenge, we used a sequential immunization model with repeated exposure of antigenically partially conserved strains of influenza viruses, revealing that Tfr cells promote recall antibody responses against the conserved HA stalk region. Thus, Tfr cells promote antigen-specific B cell responses and are essential for the development of long-term humoral memory.<\/jats:p>","DOI":"10.1084\/jem.20200547","type":"journal-article","created":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T16:28:16Z","timestamp":1608568096000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":56,"title":["CD4+ follicular regulatory T cells optimize the influenza virus\u2013specific B cell response"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7960-5445","authenticated-orcid":true,"given":"Yisi","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 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