{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T07:28:54Z","timestamp":1792740534709,"version":"4.5.0"},"reference-count":103,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T00:00:00Z","timestamp":1726099200000},"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. Immunol."],"abstract":"<jats:p>Despite decades of intense research, our understanding of the correlates of protection against <jats:italic>Salmonella<\/jats:italic> Typhi (<jats:italic>S<\/jats:italic>. Typhi) infection and disease remains incomplete. T follicular helper cells (T<jats:sub>FH<\/jats:sub>), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional T<jats:sub>FH<\/jats:sub> cells reside in germinal centers, circulating T<jats:sub>FH<\/jats:sub> (cT<jats:sub>FH<\/jats:sub>) (a memory subset of T<jats:sub>FH<\/jats:sub>) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated <jats:italic>S<\/jats:italic>. Typhi vaccine and then challenged with virulent <jats:italic>S<\/jats:italic>. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cT<jats:sub>FH<\/jats:sub> subsets in the development and prevention of typhoid disease. Of note, the frequencies of cT<jats:sub>FH<\/jats:sub> were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cT<jats:sub>FH<\/jats:sub>2 and cT<jats:sub>FH<\/jats:sub>17, but not cT<jats:sub>FH<\/jats:sub>1 subsets were higher in NoTD than TD participants. However, we observed that ex-vivo expression of activation and homing markers were higher in TD than in NoTD participants, particularly after challenge. Moreover, cT<jats:sub>FH<\/jats:sub> subsets produced higher levels of <jats:italic>S<\/jats:italic>. Typhi-specific responses (cytokines\/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cT<jats:sub>FH<\/jats:sub> subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cT<jats:sub>FH<\/jats:sub> subsets and anti-<jats:italic>S.<\/jats:italic> Typhi antibodies. Taken together, our results suggest that circulating T<jats:sub>FH<\/jats:sub>2 and T<jats:sub>FH<\/jats:sub>17 subsets might play an important role in the development or prevention of typhoid disease. The contribution of these clusters was found to be distinct in the immunization and\/or challenge phases. These results have important implications for vaccines aimed at inducing long-lived protective T cell and antibody responses.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1384642","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T12:21:55Z","timestamp":1730722915000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Role of circulating T follicular helper subsets following Ty21a immunization and oral challenge with wild type S. 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