Bordetella adenylate cyclase toxin differentially modulates toll-like receptor-stimulated activation, migration and T cell stimulatory capacity of dendritic cells

• Published in: PloS one 2014-08, Vol.9 (8), p.e104064-e104064
• Main Authors: Adkins, Irena, Kamanova, Jana, Kocourkova, Aneta, Svedova, Martina, Tomala, Jakub, Janova, Hana, Masin, Jiri, Chladkova, Barbora, Bumba, Ladislav, Kovar, Marek, Ross, Padraig J, Tuckova, Ludmila, Spisek, Radek, Mills, Kingston H G, Sebo, Peter
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Adenylate Cyclase Toxin - pharmacology; Animals; Antigens; Antigens, CD - metabolism; Biochemistry; Biology and life sciences; Bordetella pertussis; Bordetella pertussis - chemistry; CCL19 protein; CCL21 protein; CD11b antigen; CD25 antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell adhesion; Cell Adhesion - drug effects; Cell cycle; Cell Death - drug effects; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chemokines; Cough; Cyclic AMP; Cytokines; Cytosol; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Drainage; Enzymes; Foxp3 protein; Homing; Humans; Immune response; Immune system; Immunology; Immunoregulation; Infections; Interleukin 10; Interleukin 17; Laboratories; Leukocyte migration; Lymph nodes; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice, Inbred C57BL; Molecular biology; Pathogens; Peptides; Phagocytes; Proteins; Signaling; Solubility; T cells; T-Lymphocytes, Regulatory - drug effects; Toll-like receptors; Toll-Like Receptors - metabolism; Vaccines; Virulence; Virulence factors; Whooping cough; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104064

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.