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In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -T<jats:sub>M<\/jats:sub>) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (T<jats:sub>RM<\/jats:sub>) cells. T<jats:sub>RM<\/jats:sub>provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts T<jats:sub>RM<\/jats:sub><jats:italic>S<\/jats:italic>. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI<jats:italic>S.<\/jats:italic>Typhi-responsive T<jats:sub>RM<\/jats:sub>subsets elicited by Ty21a immunization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) T<jats:sub>M<\/jats:sub>and T<jats:sub>RM<\/jats:sub>in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ T<jats:sub>RM<\/jats:sub>displayed a positive correlation with age whilst the CD4\/CD8 ratio in LPMC displayed a negative correlation with age<jats:bold>.<\/jats:bold>We observed that elderly volunteers have weaker<jats:italic>S.<\/jats:italic>Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ T<jats:sub>RM<\/jats:sub>showed reduced IL-17A production, while CD103- CD4+ T<jats:sub>RM<\/jats:sub>exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ T<jats:sub>RM<\/jats:sub>and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ T<jats:sub>RM<\/jats:sub>subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Aging influences tissue resident T<jats:sub>M<\/jats:sub><jats:italic>S<\/jats:italic>. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p>This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (<jats:italic>identifier<\/jats:italic><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/home\">NCT03970304<\/jats:ext-link><jats:italic>, Registered 29 May 2019 - Retrospectively registered)<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12979-021-00227-y","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T04:02:54Z","timestamp":1618804974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans"],"prefix":"10.1186","volume":"18","author":[{"given":"Jayaum S.","family":"Booth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema A.","family":"Patil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin S.","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Greenwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo B.","family":"Sztein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"issue":"4","key":"227_CR1","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1111\/j.1365-2567.2007.02555.x","volume":"120","author":"D Aw","year":"2007","unstructured":"Aw D, Silva AB, Palmer DB. 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