title: 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 42/84days 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+ TEMand TEMRAsubsets 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.
authors.affiliation: Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Rezwanul
authors.initials: R
authors.lastname: Wahid
authors.affiliation: Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fresnay
authors.affiliation: Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: msztein@medicine.umaryland.edu.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage*; D012482:Salmonella paratyphi A / Q000276:immunology*; D012484:Salmonella paratyphi B / Q000276:immunology*; D012485:Salmonella typhi / Q000276:immunology*; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage*; D062690:Vaccines, Live, Unattenuated / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D016207:Cytokines; D011135:Polysaccharides, Bacterial; C072772:Ty21a typhoid vaccine; D014436:Typhoid-Paratyphoid Vaccines; D062690:Vaccines, Live, Unattenuated
keywords: CD4 T cells; Cross-reactive; Human; Multifunctional; Salmonella; Ty21a