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Background  The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. 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 M ) 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 RM ) cells. T RM  provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts T RM   S . Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI  S.  Typhi-responsive T RM  subsets elicited by Ty21a immunization.    Results  We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) T M  and T RM  in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ T RM  displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age .  We observed that elderly volunteers have weaker  S.  Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ T RM  showed reduced IL-17A production, while CD103- CD4+ T RM  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 RM  and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ T RM  subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.    Conclusions  Aging influences tissue resident T M   S . 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.    Trial registration  This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov ( identifier   NCT03970304  , Registered 29 May 2019 - Retrospectively registered) .    Supplementary Information  The online version contains supplementary material available at 10.1186/s12979-021-00227-y.

Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans