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Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but they have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment with Fc-fused interleukin-7 (IL-7\u2013mFc) protects mice from lethal IAV infections. The protective activity of IL-7\u2013mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7\u2013mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as tissue-resident memory-like T (T<jats:sub>RM<\/jats:sub>-like) cells. IL-7\u2013mFc-primed pulmonary T<jats:sub>RM<\/jats:sub>-like cells contribute to protection upon IAV infection by dual modes. First, T<jats:sub>RM<\/jats:sub>-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Second, T<jats:sub>RM<\/jats:sub>-like cells augment expansion of IAV-specific cytotoxic T lymphocytes (CTLs), in particular at the late phase of infection, which directly control viruses. Thus, accelerated viral clearance facilitated by pulmonary T cells, which are either antigen specific or not, alleviates immunopathology in the lung and mortality from IAV infection. Depleting a subset of pulmonary T cells indicates that both CD4 and CD8 T cells contribute to protection from IAV, although IL-7-primed CD4 T cells have a more prominent role. Collectively, we propose intranasal IL-7\u2013mFc pretreatment as an effective means for generating protective immunity against IAV infections, which could be applied to a potential prophylaxis for influenza pandemics in the future.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The major consequence of a highly pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7\u2013mFc pretreatment protected immunologically naive mice from lethal IAV infections. Intranasal pretreatment with IL-7\u2013mFc induced an infiltration of T cells in the lung, which reside as effector\/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment with IL-7\u2013mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7\u2013mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.<\/jats:p>","DOI":"10.1128\/jvi.02768-15","type":"journal-article","created":{"date-parts":[[2015,12,11]],"date-time":"2015-12-11T12:54:04Z","timestamp":1449838444000},"page":"2273-2284","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection"],"prefix":"10.1128","volume":"90","author":[{"given":"Moon Cheol","family":"Kang","sequence":"first","affiliation":[{"name":"Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of 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