Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a

Abstract

The live oral typhoid vaccine Ty21a elicits predominantly CD8+, as well as CD4+ T cells mediated immune responses. Clinical field studies showed that Ty21a is moderately effective against S. Typhi and S. Paratyphi B, but not S. Paratyphi A infections. In this study we describe the in depth characterization of S. Typhi, S. Paratyphi A and S. Paratyphi B cross-reactive CD4+ T cell responses elicited following immunization with Ty21a. PBMC samples were collected from 16 healthy volunteers before and 42/84 days after Ty21a immunization and stimulated ex-vivo with Salmonella-infected targets. Multiparametric flow cytometry was used to detect the vaccine elicited Salmonella-specific responses in T effector/memory (TEM) and CD45RA+ T effector/memory (TEMRA) CD4+ cell subsets, by measuring CD4+ multifunctional (MF) cells that concomitantly produced IFN-γ, TNF-α, IL-2, MIP-1β, IL-17A and/or expressed CD107a. Post-vaccination increases in S. Typhi-specific MF cells were observed in CD4+ TEM and TEMRA subsets which predominantly produced IFN-γ and/or TNF-α, while IL-2 was produced by a smaller cell subset. A small proportion of those MF cells also produced MIP-1β, IL-17A and expressed CD107a (a marker associated with cytotoxicity). Approximately one third of these specific MF cells have the potential to migrate to the gut mucosa, as evidenced by co-expression of the gut-homing molecule integrin α4β7. In contrast to our previous observations with CD8+T cells, MF CD4+ T cell responses to the different Salmonella serovars evaluated were similar in magnitude and characteristics. We conclude that although induction of cross-reactive CD4+ MF effector T cells suggest a possible role in Salmonella-immunity, these responses are unlikely to provide an immunological basis for the observed efficacy of Ty21a against S. Typhi and S. Paratyphi B, but not to S. Paratyphi A.

Evolution of Salmonella Typhi outer membrane protein-specific T and B cell responses in humans following oral Ty21a vaccination: A randomized clinical trial

“…Moreover, we found that volunteers vaccinated with Ty21a generated OmpC and F specific CD4 + T cells with a multifunctional cytokine production profile. These findings are in line with the finding that Ty21a vaccination elicits multifunctional CD4 + and CD8 + T cell responses against multiple antigens [10, 14]. Our results suggest that a substantial fraction of multifunctional CD4 + T cells recognize OmpC and F porins following vaccination with Ty21a and–most likely–during S .…”

Salmonella Virulence and Immune Escape

“…Both CD4 + and CD8 + T lymphocytes and the humoral immune responses are required to control Salmonella infection [242][243][244][245][246][247][248]. It has been demonstrated that mice continuously infected with Salmonella have higher antibody titers [232] including IgA, IgM, and IgG [232,249], indicating that B cells also play an important role in the host defense.…”

Human Salmonella Typhi exposure generates differential multifunctional cross‐reactive T‐cell memory responses against Salmonella Paratyphi and invasive nontyphoidal Salmonella

“…That a high proportion of these induced multifunctional CD8 + T cells do not express integrin a4b7 supports similar data we have previously reported in volunteers immunised with attenuated S. Typhi vaccines. 31,56,57 These results underscore the increased presence in circulation of memory T cells elicited in S. Typhi-challenged adults with the ability to home to mucosal and other systemic tissues, which may prevent dissemination during future Salmonella infections.…”