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Whether parenteral SARS-CoV-2 vaccination or infection induces nasal-resident T cells specific for distinct SARS-CoV-2 proteins is unknown. We isolated T cells from the nasal mucosa of COVID-19 vaccinees who either experienced SARS-CoV-2 infection after vaccination (n = 34) or not (n = 16) and analyzed their phenotype, SARS-CoV-2 specificity, function, and persistence. Nasal-resident SARS-CoV-2\u2013specific CD8+ and CD4+ T cells were detected almost exclusively in vaccinees who experienced SARS-CoV-2 breakthrough infection. Importantly, the Spike-specific T cells primed by vaccination did not suppress the induction of T cells specific for other SARS-CoV-2 proteins. The nasal-resident T cell responses persisted for \u2265140 d, with minimal sign of waning. These data highlight the importance of viral nasal challenge in the formation of SARS-CoV-2\u2013specific antiviral immunity at the site of primary infection and further define the immunological features of SARS-CoV-2 hybrid immunity.<\/jats:p>","DOI":"10.1084\/jem.20220780","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T02:21:03Z","timestamp":1659579663000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":125,"title":["SARS-CoV-2 breakthrough infection in vaccinees induces virus-specific nasal-resident CD8+ and CD4+ T cells of broad specificity"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4775-2376","authenticated-orcid":true,"given":"Joey Ming Er","family":"Lim","sequence":"first","affiliation":[{"name":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0079-8203","authenticated-orcid":true,"given":"Anthony Tanoto","family":"Tan","sequence":"additional","affiliation":[{"name":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0502-2527","authenticated-orcid":true,"given":"Nina","family":"Le Bert","sequence":"additional","affiliation":[{"name":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4169-7209","authenticated-orcid":true,"given":"Shou Kit","family":"Hang","sequence":"additional","affiliation":[{"name":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3876-2209","authenticated-orcid":true,"given":"Jenny Guek Hong","family":"Low","sequence":"additional","affiliation":[{"name":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 1"},{"name":"Department of Infectious Disease, Singapore General Hospital, Singapore 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2942-0485","authenticated-orcid":true,"given":"Antonio","family":"Bertoletti","sequence":"additional","affiliation":[{"name":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"2022081613491305000_bib1","doi-asserted-by":"publisher","first-page":"148517","DOI":"10.1172\/jci148517","article-title":"Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19","volume":"131","author":"Ahn","year":"2021","journal-title":"J. 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