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

Despite decades of intense research, our understanding of the correlates of protection against Typhi (. Typhi) infection and disease remains incomplete. T follicular helper cells (T), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional T cells reside in germinal centers, circulating T (cT) (a memory subset of T) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated . Typhi vaccine and then challenged with virulent . Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cT subsets in the development and prevention of typhoid disease. Of note, the frequencies of cT were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cT2 and cT17, but not cT1 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 subsets produced higher levels of . Typhi-specific responses (cytokines/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cT subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cT subsets and anti- Typhi antibodies. Taken together, our results suggest that circulating T2 and T17 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.