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Immunological memory to coronaviruses can be cross-reactive for multiple coronaviruses including OC43 and SARS-CoV-2. In this study, we used mouse models to investigate immune responses elicited by pulmonary infection with OC43. OC43 caused a mild, self-limiting infection. Early after infection, there was acute influx of myeloid cells and lymphocytes to the lung as well as a type I interferon\u2013dependent production of IFN-\u03b3. However, blocking interferons did not enhance viral infection. After recovery, lungs contained resident memory lymphocytes, and both the blood and lungs contained antibodies against OC43. When infection was supplemented with proinflammatory stimuli to model more severe disease, OC43-elicited immune changes were bolstered, including increased virus-specific plasma IgG and lung IgA, enhanced lung B-cell class-switching, and increased antigen-specific Th1 and Th17 cytokine production from lung CD4+ T cells. The antibodies and CD4+ T cells in mice recovered from OC43 infection, even with immunostimulatory agents, reacted only with OC43 proteins and peptides and not with those from other coronaviruses. Therefore, OC43 infection in wild-type mice does not induce the heterotypic immunity observed in humans. In conclusion, OC43 induces a self-limiting lung infection in mice accompanied by homotypic lung-resident and systemic memory, amplified by proinflammatory stimuli during infection.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag182","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T16:31:19Z","timestamp":1784133079000},"source":"Crossref","is-referenced-by-count":0,"title":["Systemic and lung-resident memory elicited by OC43 coronavirus infection in mice"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3720-2848","authenticated-orcid":false,"given":"Nathan L","family":"Sanders","sequence":"first","affiliation":[{"name":"Pulmonary Center, Boston University Chobanian and Avedisian School of Medicine , Boston, MA,","place":["United States"]},{"name":"Department of Virology, Immunology, and Microbiology, Boston University Chobanian and Avedisian School of Medicine , Boston, MA,","place":["United States"]},{"name":"National 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