AUTHOR=Booth Jayaum S. , Rapaka Rekha R. , McArthur Monica A. , Fresnay Stephanie , Darton Thomas C. , Blohmke Christoph J. , Jones Claire , Waddington Claire S. , Levine Myron M. , Pollard Andrew J. , Sztein Marcelo B. 

TITLE=Role of circulating T follicular helper subsets following Ty21a immunization and oral challenge with wild type S. Typhi in humans

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1384642

DOI=10.3389/fimmu.2024.1384642

ISSN=1664-3224

ABSTRACT=<p>Despite decades of intense research, our understanding of the correlates of protection against <italic>Salmonella</italic> Typhi (<italic>S</italic>. Typhi) infection and disease remains incomplete. T follicular helper cells (T<sub>FH</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<sub>FH</sub> cells reside in germinal centers, circulating T<sub>FH</sub> (cT<sub>FH</sub>) (a memory subset of T<sub>FH</sub>) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated <italic>S</italic>. Typhi vaccine and then challenged with virulent <italic>S</italic>. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cT<sub>FH</sub> subsets in the development and prevention of typhoid disease. Of note, the frequencies of cT<sub>FH</sub> were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cT<sub>FH</sub>2 and cT<sub>FH</sub>17, but not cT<sub>FH</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<sub>FH</sub> subsets produced higher levels of <italic>S</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<sub>FH</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<sub>FH</sub> subsets and anti-<italic>S.</italic> Typhi antibodies. Taken together, our results suggest that circulating T<sub>FH</sub>2 and T<sub>FH</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.</p>