title: Bordetella adenylate cyclase toxin differentially modulates toll-like receptor-stimulated activation, migration and T cell stimulatory capacity of dendritic cells.
abstract: Adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. The toxin targets CD11b-expressing phagocytes and delivers into their cytosol an adenylyl cyclase (AC) enzyme that subverts cellular signaling by increasing cAMP levels. In the present study, we analyzed the modulatory effects of CyaA on adhesive, migratory and antigen presenting properties of Toll-like receptor (TLR)-activated murine and human dendritic cells (DCs). cAMP signaling of CyaA enhanced TLR-induced dissolution of cell adhesive contacts and migration of DCs towards the lymph node-homing chemokines CCL19 and CCL21 in vitro. Moreover, we examined in detail the capacity of toxin-treated DCs to induce CD4(+) and CD8(+) T cell responses. Exposure to CyaA decreased the capacity of LPS-stimulated DCs to present soluble protein antigen to CD4+ T cells independently of modulation of co-stimulatory molecules and cytokine production, and enhanced their capacity to promote CD4(+)CD25(+)Foxp3(+) T regulatory cells in vitro. In addition, CyaA decreased the capacity of LPS-stimulated DCs to induce CD8(+) T cell proliferation and limited the induction of IFN-γ producing CD8(+) T cells while enhancing IL-10 and IL-17-production. These results indicate that through activation of cAMP signaling, the CyaA may be mobilizing DCs impaired in T cell stimulatory capacity and arrival of such DCs into draining lymph nodes may than contribute to delay and subversion of host immune responses during B. pertussis infection.
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Adkins
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kamanova
authors.affiliation: Institute of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Aneta
authors.initials: A
authors.lastname: Kocourkova
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Svedova
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tomala
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Janova
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Masin
authors.affiliation: Laboratory of Specific Cellular Immunity, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Chladkova
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Bumba
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Kovar
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
authors.forename: Padraig J
authors.initials: PJ
authors.lastname: Ross
authors.affiliation: Laboratory of Specific Cellular Immunity, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Tuckova
authors.affiliation: Institute of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Spisek
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.affiliation: Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Sebo
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001886:Bordetella pertussis / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D012995:Solubility; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D037361:Adenylate Cyclase Toxin; D015703:Antigens, CD; D051193:Toll-Like Receptors
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