title: Systemic flagellin immunization stimulates mucosal CD103+ dendritic cells and drives Foxp3+ regulatory T cell and IgA responses in the mesenteric lymph node.
abstract: Mucosal immunity is poorly activated after systemic immunization with protein Ags. Nevertheless, induction of mucosal immunity in such a manner would be an attractive and simple way to overcome the intrinsic difficulties in delivering Ag to such sites. Flagellin from Salmonella enterica serovar Typhimurium (FliC) can impact markedly on host immunity, in part via its recognition by TLR5. In this study, we show that systemic immunization with soluble FliC (sFliC) drives distinct immune responses concurrently in the mesenteric lymph nodes (MLN) and the spleen after i.p. and s.c. immunization. In the MLN, but not the spleen, sFliC drives a TLR5-dependent recruitment of CD103(+) dendritic cells (DCs), which correlates with a diminution in CD103(+) DC numbers in the lamina propria. In the MLN, CD103(+) DCs carry Ag and are the major primers of endogenous and transgenic T cell priming. A key consequence of these interactions with CD103(+) DCs in the MLN is an increase in local regulatory T cell differentiation. In parallel, systemic sFliC immunization results in a pronounced switching of FliC-specific B cells to IgA in the MLN but not elsewhere. Loss of TLR5 has more impact on MLN than splenic Ab responses, reflected in an ablation of IgA, but not IgG, serum Ab titers. Therefore, systemic sFliC immunization targets CD103(+) DCs and drives distinct mucosal T and B cell responses. This offers a potential "Trojan horse" approach to modulate mucosal immunity by systemically immunizing with sFliC.
authors.affiliation: Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Adriana
authors.initials: A
authors.lastname: Flores-Langarica
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Jessica
authors.initials: J
authors.lastname: Hitchcock
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cook
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jobanputra
authors.forename: Saeeda
authors.initials: S
authors.lastname: Bobat
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Coughlan
authors.forename: Ian R
authors.initials: IR
authors.lastname: Henderson
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005408:Flagellin / Q000008:administration & dosage* / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000502:physiology; D007114:Immunization; D007070:Immunoglobulin A / Q000096:biosynthesis*; D039001:Integrin alpha Chains / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008643:Mesentery; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012480:Salmonella Infections / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012486:Salmonella typhimurium; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007070:Immunoglobulin A; D039001:Integrin alpha Chains; C091367:alpha E integrins; D005408:Flagellin