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Exploiting a mouse model of vaccination, we show that the spleens of C57BL\/6 mice vaccinated with live-attenuated<jats:italic>Salmonella<\/jats:italic>serovar Typhimurium (<jats:italic>S<\/jats:italic>. Typhimurium) strains carried a pool of IFN-\u03b3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells that could adoptively transfer protection, but only transiently. Circulating<jats:italic>Salmonella<\/jats:italic>-reactive CD4<jats:sup>+<\/jats:sup>T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4<jats:sup>+<\/jats:sup>T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4<jats:sup>+<\/jats:sup>T cells mediating immunity to<jats:italic>Salmonella<\/jats:italic>is limited to a brief window after which<jats:italic>Salmonella<\/jats:italic>-specific CD4<jats:sup>+<\/jats:sup>T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010004","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T17:31:46Z","timestamp":1635183106000},"page":"e1010004","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["CD4+ T cell immunity to Salmonella is transient in the circulation"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6681-1469","authenticated-orcid":true,"given":"Newton 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