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However, the underlying immune mechanisms governing these interactions remain poorly understood. In this study, we examined whether respiratory syncytial virus (RSV) infection modulates host susceptibility to subsequent SARS-CoV-2 infection using two murine models. We found that prior RSV infection conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Transcriptomic and immunological analyses revealed that RSV activated lung antigen-presenting cells (APCs) and SARS-CoV-2\u2013reactive mucosal T cells by day 9 post-infection, with responses waning by 1 month. RSV also promoted expansion of pulmonary \u03b3\u03b4 T cells and upregulation of their metabolic pathways. Notably, RSV-infected TCR\u03b4\u207b\n                      <jats:sup>\/<\/jats:sup>\n                      \u207b mice, which lack \u03b3\u03b4 T cells, exhibited diminished SARS-CoV-2\u2013reactive mucosal T cell responses, elevated viral loads, and exacerbated lung inflammation following SARS-CoV-2 challenge compared to wild-type controls. These findings suggest that RSV infection induces \u03b3\u03b4 T cell-mediated trained immunity and primes mucosal T cell responses, thereby providing heterologous protection against SARS-CoV-2.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>The mechanisms by which prior respiratory viral infections confer heterologous protection remain largely undefined. In this study, we investigated whether respiratory syncytial virus (RSV) infection influences host susceptibility to subsequent SARS-CoV-2 infection in mice. We found that prior RSV exposure conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Mechanistically, RSV infection induces \u03b3\u03b4 T cell-mediated trained immunity, enhances antigen-presenting cell activation, and promotes the generation of SARS-CoV-2\u2013reactive mucosal T cells. Together, these immune responses contribute to cross-protective immunity against SARS-CoV-2. Our findings offer new insights into the immunological interplay between co-circulating respiratory viruses and SARS-CoV-2, with implications for future vaccine design and pandemic preparedness.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01658-25","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T13:06:52Z","timestamp":1773839212000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Respiratory syncytial virus infection induces heterologous protection against SARS-CoV-2 through \u03b3\u03b4 T cell-mediated trained immunity and the activation of SARS-CoV-2\u2013reactive mucosal T cells"],"prefix":"10.1128","volume":"100","author":[{"given":"Awadalkareem","family":"Adam","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016tfm930","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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