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We previously demonstrated that the Hup protein of Staphylococcus and Streptococcus species harbors a shared CD4+ T cell epitope, and that Hup77\u201388-specific CD4+ T cells confer cross-species protection against pulmonary infection with these bacteria. Here, we investigated whether exposure to the Gram-positive intracellular pathogen Listeria monocytogenes, that expresses an orthologous Hup protein, induces a Hup-specific CD4+ T cell response. Live L. monocytogenes infection in mice generated detectable but modest Hup78\u201389-specific CD4+ T cell responses. In contrast, immunization with heat-killed L. monocytogenes or infection with a listeriolysin O\u2013deficient strain, induced robust Hup78\u201389-specific Th17 responses. Despite their expansion, heat-killed L. monocytogenes\u2013induced Hup-specific CD4+ T cells did not protect against secondary L. monocytogenes challenge, consistent with the requirement for T helper 1 and CD8+ T cell immunity for anti-Listeria protection. However, these CD4+ T cells conferred protection against pulmonary infection with Staphylococcus aureus expressing the L. monocytogenes Hup epitope. These findings establish Hup as conserved CD4+ T cell antigen target across bacterial species and demonstrates that T cell polarization and pathogen lifecycle are critical considerations when designing pan-antibacterial vaccines targeting shared bacterial antigens.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag253","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:53:25Z","timestamp":1790625205000},"source":"Crossref","is-referenced-by-count":0,"title":["Live versus killed\n                    <i>Listeria monocytogenes<\/i>\n                    immunization differentially programs Hup-specific CD4+ T cell responses with distinct protective outcomes"],"prefix":"10.1093","volume":"215","author":[{"given":"Jessica","family":"Braverman","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R","family":"Monk","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh Anh","family":"To","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, Victoria,","place":["Australia"]},{"name":"Enteric Diseases Research Group, Murdoch Children\u2019s Research Institute , Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P","family":"Stinear","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, Victoria,","place":["Australia"]},{"name":"Centre for Pathogen Genomics, University of Melbourne , Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M","family":"Wakim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, 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