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

摘要

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 (T-EM) and CD45RA+ T effector/memory (T-EMRA) CD4+ cell subsets, by measuring CD4+ multifunctional (MF) cells that concomitantly produced IFN-gamma, TNF-alpha, IL-2, MIP-1 beta, IL-17A and/or expressed CD107a. Post-vaccination increases in S. Typhi-specific MF cells were observed in CD4+ T-EM and T-EMRA subsets which predominantly produced IFN-gamma and/or TNF-alpha, while IL-2 was produced by a smaller cell subset. A small proportion of those MF cells also produced MIP-1 beta, 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 alpha(4)beta(7). 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. (C) 2016 Elsevier Inc. All rights reserved.