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

Irena Adkins; Jana Kamanova; Aneta Kocourkova; Martina Svedova; Jakub Tomala; Hana Janova; Jiri Masin; Barbora Chladkova; Ladislav Bumba; Marek Kovar; Padraig J Ross; Ludmila Tuckova; Radek Spisek; Kingston H G Mills; Peter Sebo

doi:10.1371/journal.pone.0104064

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

PLoS One. 2014 Aug 1;9(8):e104064. doi: 10.1371/journal.pone.0104064. eCollection 2014.

Authors

Affiliations

¹ Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
² Institute of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
³ Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
⁴ Laboratory of Specific Cellular Immunity, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
⁵ Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenylate Cyclase Toxin / pharmacology*
Animals
Antigens, CD / metabolism
Bordetella pertussis / chemistry*
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cell Adhesion / drug effects
Cell Death / drug effects
Cell Movement / drug effects*
Cell Proliferation / drug effects
Dendritic Cells / cytology*
Dendritic Cells / drug effects
Dendritic Cells / immunology*
Humans
Lymphocyte Activation / drug effects*
Mice, Inbred C57BL
Solubility
T-Lymphocytes, Regulatory / drug effects
Toll-Like Receptors / metabolism*

Substances

Adenylate Cyclase Toxin
Antigens, CD
Toll-Like Receptors

Grants and funding

This work was supported by the grant No. GA310/08/0447 (to PS), No. GA310/09/P582 (to IA) and No. P301/11/0325 (to MK) of the National Science Foundation of the Czech Republic, the Research center 1M0506, and by research grant IGA NT12402-5 from the Czech Ministry of Health. KM and PR are supported by a principal investigator grant (06/IN.1/B87) from Science Foundation Ireland. MS was a recipient of a stipend from the Ministry of Education of Czech Republic and of the support from the Specific Research Project No. 33779266 of the Charles University in Prague, Czech Republic. The support from a FEBS short-term fellowship granted to IA is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.