{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:56:04Z","timestamp":1790916964992,"version":"4.1.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells are essential components of the adaptive immune system that play a critical role in determining the clinical severity of typhoid disease by directly killing\n                      <jats:italic>Salmonella enterica<\/jats:italic>\n                      serovar Typhi (\n                      <jats:italic>S<\/jats:italic>\n                      . Typhi)-infected cells, producing cytokines, chemokines, and establishing memory responses that have been linked to clinical outcome in a controlled human infection model (CHIM) of typhoid. Despite decades of extensive research, the role of memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T (T\n                      <jats:sub>M<\/jats:sub>\n                      ) cells and its subsets as correlates of protection against\n                      <jats:italic>S<\/jats:italic>\n                      . Typhi infection and typhoid disease remains incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we used specimens from a typhoid CHIM study in which participants who were immunized with live attenuated\n                      <jats:italic>S<\/jats:italic>\n                      . Typhi vaccine, Ty21a, were subsequently challenged with virulent\n                      <jats:italic>S<\/jats:italic>\n                      . Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), allowing us to assess the immune program of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>M<\/jats:sub>\n                      subsets involved in the prevention of typhoid disease using mass cytometry, CyTOF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and discussion<\/jats:title>\n                    <jats:p>\n                      Our high-dimensional profiling data showed that TD and NoTD participants followed divergent memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell trajectories. We observed that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T clusters from NoTD participants are enriched for early multifunctional, protection-associated programs while TD participants exhibited a distinct clustering associated with susceptibility states. Specifically, using unsupervised dimensionality reduction and clustering analysis, T-REX, and feature-ranking analyses, we identified memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subsets including effector\/memory (T\n                      <jats:sub>EM<\/jats:sub>\n                      ), T central\/memory (T\n                      <jats:sub>CM<\/jats:sub>\n                      ) and CD45RA+ T\n                      <jats:sub>EM<\/jats:sub>\n                      (T\n                      <jats:sub>EMRA<\/jats:sub>\n                      ) associated with clinical outcomes. CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>EM<\/jats:sub>\n                      from NoTD participants were generally characterized by stronger effector-associated signatures such as CXCR3, IL-17A, TNF\u03b1, and MIP1b. In contrast, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>EM<\/jats:sub>\n                      from TD participants showed CCR6- and integrin \u03b14\u03b27-biased immune profiles. Detailed analysis revealed that CD8\u207a T\n                      <jats:sub>CM<\/jats:sub>\n                      and T\n                      <jats:sub>EMRA<\/jats:sub>\n                      subsets also contained distinct outcome-associated states. These patterns were confirmed by conventional supervised gating that validated both protection-associated and susceptibility-associated marker combinations across CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>EM<\/jats:sub>\n                      , T\n                      <jats:sub>CM<\/jats:sub>\n                      and T\n                      <jats:sub>EMRA<\/jats:sub>\n                      subsets. These data suggest that: 1. Protection and susceptibility are not restricted to one CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subset but rather are distributed across the broader CD8\n                      <jats:sup>+<\/jats:sup>\n                      T memory landscape and, 2. Typhoid clinical outcome is associated with qualitatively distinct CD8\n                      <jats:sup>+<\/jats:sup>\n                      T memory programs rather than differences only in the magnitude of the overall anti-\n                      <jats:italic>S<\/jats:italic>\n                      . Typhi immune response.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1924754","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:39:33Z","timestamp":1790915973000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct time-dependent S. Typhi-specific CD8+ T cell programs are associated with clinical outcome following Ty21a immunization and wild-type S. 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