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* Istituto Superiore di Sanità, Department of Infectious, Parasitic and Immune-mediated Diseases, Rome, Italy; and
Novartis Vaccines and Diagnostics, Siena, Italy
Genetically detoxified pertussis toxin (dPT) maintains the protein structure and the immunological properties, but not the enzymatic activity. In search of an adjuvant able to direct polarization of T cells to induce/potentiate protective immune response to a variety of infectious disease, we investigated the role played by dPT on human dendritic cell-driven Th polarization and analyzed the intracellular signaling events. To reach these aims, we used a highly purified dPT preparation devoid of contamination and monocyte-derived dendritic cells, a well-characterized model to study ex vivo the polarization of the immune responses. First, we analyzed dPT-induced monocyte-derived dendritic cell maturation, longevity, and cytokine production and, in a second step, we analyzed TLR4/2 engagement by dPT, the connected signaling events, and their relevance to the skewing of Th cell polarization. These approaches allowed us to clarify some of the mechanisms that are responsible for dPT-driven regulation of T cell polarization. We demonstrated that dPT acts utilizing TLR4/TLR2 engagement, being the signaling induced by the former stronger. dPT, through a crucial role played by MAPK and IL-10, favors the expansion of the Th1/Th17 immunity. Indirect evidences indicated that dPT-induced Th17 expansion is counterregulated by the PI3K pathway. For its properties and being already used in humans as vaccine Ag in pertussis, dPT may represents a valid candidate adjuvant to foster immune protective response in vaccines against infectious diseases where Th1/Th17 are mediating host immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Istituto Superiore di Sanità-National Institutes of Health-USA scientific cooperation agreement (nos. 5303 and 28C6); Italian Ministry of Health Ricerca Finalizzata and Agenzia Italiana del Farmaco; the Istituto Superiore di Sanità, 6th AIDS project to C.M.A.; and the Commission of the European Communities, Contract LSHP-CT-2003-503240, Mucosal Vaccines for Poverty-Related Diseases, and Contract 201502, Nasal Vaccination against Respiratory Infections in Young Children (ChildINNOVAC).
2 M.N. and G.F. contributed equally to this study.
3 Current address: FS Novartis Vaccines and Diagnostics, Siena, Italy.
4 Address correspondence and reprint requests to Dr. Clara Maria Ausiello, Istituto Superiore di Sanità, Department of Infectious, Parasitic and Immune-mediated Diseases, Anti-infectious Immunity Unit, Viale Regina Elena, 299 00161 Rome, Italy. E-mail address: clara.ausiello{at}iss.it
5 Abbreviations used in this paper: DC, dendritic cell; dPT, genetically detoxified pertussis toxin; MDDC, monocyte-derived DC; HEK, human epithelial kidney; Pam2CSK4, S-[2,3-bis(palmitoloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine X 3CF3COOH; SEAP, secreted alkaline phosphatase; SAPK, stress-activated protein kinase; IP-10, IFN-inducible protein; MFI, mean fluorescence intensity; IRF-1, IFN regulatory protein 1.
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