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Antibody responses are diminished in early life, limiting long-term protective immunity and allowing prolonged or recurrent infection, which may be important for viral lung infections that are highly prevalent in infancy. In a murine model using respiratory syncytial virus (RSV), we show that TFH and the high-affinity antibody production they promote are vital for preventing disease on RSV reinfection. Following a secondary RSV infection, TFH-deficient mice had significantly exacerbated disease characterized by delayed viral clearance, increased weight loss, and immunopathology. TFH generation in early life was compromised by heightened IL-2 and STAT5 signaling in differentiating naive T cells. Neutralization of IL-2 during early-life RSV infection resulted in a TFH-dependent increase in antibody-mediated immunity and was sufficient to limit disease severity upon reinfection. These data demonstrate the importance of TFH in protection against recurrent RSV infection and highlight a mechanism by which this is suppressed in early life.<\/jats:p>","DOI":"10.1084\/jem.20201555","type":"journal-article","created":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T02:22:00Z","timestamp":1632450120000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-1134","authenticated-orcid":true,"given":"Chloe J.","family":"Pyle","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, South Kensington, London, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7701-8143","authenticated-orcid":true,"given":"Lucia","family":"Labeur-Iurman","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, South Kensington, London, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5594-9526","authenticated-orcid":true,"given":"Helen T.","family":"Groves","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Imperial College London, St. Mary\u2019s Campus, London, UK 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2058-8521","authenticated-orcid":true,"given":"Franz","family":"Puttur","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, South Kensington, London, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8977-6726","authenticated-orcid":true,"given":"Clare M.","family":"Lloyd","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, South Kensington, London, UK 1"},{"name":"Asthma UK Centre in Allergic Mechanisms for Asthma, London, UK 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-8741","authenticated-orcid":true,"given":"John S.","family":"Tregoning","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Imperial College London, St. Mary\u2019s Campus, London, UK 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0301-6898","authenticated-orcid":true,"given":"James A.","family":"Harker","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, South Kensington, London, UK 1"},{"name":"Asthma UK Centre in Allergic Mechanisms for Asthma, London, UK 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"2023072610102599000_bib1","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/nri1394","article-title":"Neonatal adaptive immunity comes of age","volume":"4","author":"Adkins","year":"2004","journal-title":"Nat. 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