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Recent studies have come to conflicting results regarding the contributions of Ag and\/or inflammation to memory CD8 T-cell activation. Additionally, research has indicated that inflammation-driven CD8 T-cell responses during un-related infections (bystander activation) have the potential to provide protection, but whether protection occurs in immuno-competent hosts is unclear. To investigate these questions, we examined activation of virus-specific memory CD8 T-cells following infection with <jats:italic>L. monocytogenes<\/jats:italic> either expressing or not cognate Ag. We show that Ag and inflammation act synergistically <jats:italic>in vitro<\/jats:italic> to induce memory activation. <jats:italic>In vivo<\/jats:italic>, we found that when memory CD8 T-cells significantly contribute to clearance of infection, early activation and continued responses by these cells are enhanced by cognate Ag recognition. Mechanistically, we show that bystander responses by memory are dependent upon the dose of infection and the amount of inflammation elicited following infection and are able to provide protection in IFN-\u03b3 deficient mice, but not in immuno-competent hosts. The data elucidate the requirements for memory CD8 T-cell activation and the protective role of bystander responses.<\/jats:p>","DOI":"10.1038\/srep18022","type":"journal-article","created":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T13:09:48Z","timestamp":1449752988000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Antigen-dependent and \u2013independent contributions to primary memory CD8 T cell activation and protection following infection"],"prefix":"10.1038","volume":"5","author":[{"given":"Matthew D.","family":"Martin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir P.","family":"Badovinac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,12,10]]},"reference":[{"key":"BFsrep18022_CR1","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1146\/annurev.immunol.18.1.275","volume":"18","author":"JT Harty","year":"2000","unstructured":"Harty, J. 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