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

Abstract

Despite decades of intense research, our understanding of the correlates of protection against Salmonella Typhi (S. Typhi) infection and disease remains incomplete. T follicular helper cells (T_FH), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional T_FH cells reside in germinal centers, circulating T_FH (cT_FH) (a memory subset of T_FH) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated S. Typhi vaccine and then challenged with virulent S. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cT_FH subsets in the development and prevention of typhoid disease. Of note, the frequencies of cT_FH were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cT_FH2 and cT_FH17, but not cT_FH1 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_FH subsets produced higher levels of S. Typhi-specific responses (cytokines/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cT_FH subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cT_FH subsets and anti-S. Typhi antibodies. Taken together, our results suggest that circulating T_FH2 and T_FH17 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.

Keywords: CHIM; S. Typhi; cTfh; circulating follicular helper T cells; typhoid fever.