Adenylate Cyclase Toxin from Bordetella pertussis Synergizes with Lipopolysaccharide To Promote Innate Interleukin-10 Production and Enhances the Induction of Th2 and Regulatory T Cells
Date
2004-03Author
Ross, Pádraig J.
Lavelle, Ed C.
Mills, Kingston H. G.
Boyd, Aoife P.
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Ross, Pádraig J., Lavelle, Ed C., Mills, Kingston H. G., & Boyd, Aoife P. (2004). Adenylate Cyclase Toxin from Bordetella pertussis Synergizes with Lipopolysaccharide To Promote Innate Interleukin-10 Production and Enhances the Induction of Th2 and Regulatory T Cells. Infection and Immunity, 72(3), 1568-1579. doi: 10.1128/iai.72.3.1568-1579.2004
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Abstract
Adenylate cyclase toxin (CyaA) from Bordetella pertussis can subvert host immune responses allowing
bacterial colonization. Here we have examined its adjuvant and immunomodulatory properties and the
possible contribution of lipopolysaccharide (LPS), known to be present in purified CyaA preparations. CyaA
enhanced antigen-specific interleukin-5 (IL-5) and IL-10 production and immunoglobulin G1 antibodies to
coadministered antigen in vivo. Antigen-specific CD4 + -T-cell clones generated from mice immunized with
antigen and CyaA had cytokine profiles characteristic of Th2 or type 1 regulatory T (Tr1) cells. Since innate
immune cells direct the induction of T-cell subtypes, we examined the influence of CyaA on activation of
dendritic cells (DC) and macrophages. CyaA significantly augmented LPS-induced IL-6 and IL-10 and inhibited
LPS-driven tumor necrosis factor alpha and IL-12p70 production from bone marrow-derived DC and
macrophages. CyaA also enhanced cell surface expression of CD80, CD86, and major histocompatibility class
II on immature DC. The stimulatory activity of our CyaA preparation for IL-10 production and CD80, CD86,
and major histocompatibility complex class II expression was attenuated following the addition of polymyxin
B or with the use of DC from Toll-like receptor (TLR) 4-defective mice. However, treatment of DC with LPS
alone at the concentration present in the CyaA preparation (0.2 ng/ml) failed to activate DC in vitro. Our
findings demonstrate that activation of innate cells in vitro by CyaA is dependent on a second signal through
a TLR and that CyaA can promote Th2/Tr1-cell responses by inhibiting IL-12 and promoting IL-10 production
by DC and macrophages.