title: Soluble flagellin, FliC, induces an Ag-specific Th2 response, yet promotes T-bet-regulated Th1 clearance of Salmonella typhimurium infection.
abstract: Clearance of disseminated Salmonella infection requires bacterial-specific Th1 cells and IFN-γ production, and Th1-promoting vaccines are likely to help control these infections. Consequently, vaccine design has focused on developing Th1-polarizing adjuvants or Ag that naturally induce Th1 responses. In this study, we show that, in mice, immunization with soluble, recombinant FliC protein flagellin (sFliC) induces Th2 responses as evidenced by Ag-specific GATA-3, IL-4 mRNA, and protein induction in CD62L(lo) CD4(+) T cells without associated IFN-γ production. Despite these Th2 features, sFliC immunization can enhance the development of protective Th1 immunity during subsequent Salmonella infection in an Ab-independent, T-cell-dependent manner. Salmonella infection in sFliC-immunized mice resulted in augmented Th1 responses, with greater bacterial clearance and increased numbers of IFN-γ-producing CD4(+) T cells, despite the early induction of Th2 features to sFliC. The augmented Th1 immunity after sFliC immunization was regulated by T-bet although T-bet is dispensable for primary responses to sFliC. These findings show that there can be flexibility in T-cell responses to some subunit vaccines. These vaccines may induce Th2-type immunity during primary immunization yet promote Th1-dependent responses during later infection. This suggests that designing Th1-inducing subunit vaccines may not always be necessary since this can occur naturally during subsequent infection.
authors.affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, UK.
authors.forename: Saeeda
authors.initials: S
authors.lastname: Bobat
authors.forename: Adriana
authors.initials: A
authors.lastname: Flores-Langarica
authors.forename: Jessica
authors.initials: J
authors.lastname: Hitchcock
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kingsley
authors.forename: Margaret
authors.initials: M
authors.lastname: Goodall
authors.forename: Cristina
authors.initials: C
authors.lastname: Gil-Cruz
authors.forename: Karine
authors.initials: K
authors.lastname: Serre
authors.forename: Denisse L
authors.initials: DL
authors.lastname: Leyton
authors.forename: Shirdi E
authors.initials: SE
authors.lastname: Letran
authors.forename: Fabrina
authors.initials: F
authors.lastname: Gaspal
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chester
authors.forename: Jayne L
authors.initials: JL
authors.lastname: Chamberlain
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Constantino
authors.initials: C
authors.lastname: López-Macías
authors.forename: Ian R
authors.initials: IR
authors.lastname: Henderson
authors.forename: James
authors.initials: J
authors.lastname: Alexander
authors.forename: Ian C M
authors.initials: IC
authors.lastname: MacLennan
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001428:Bacterial Vaccines; D002478:Cells, Cultured; D005408:Flagellin / Q000276:immunology*; D005786:Gene Expression Regulation; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D001428:Bacterial Vaccines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D005408:Flagellin; D007371:Interferon-gamma