Genetically detoxified pertussis toxin induces Th1/Th17 immune response through MAPKs and IL-10-dependent mechanisms.
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.
Nasso
Maria
M
Department of Infectious, Istituto Superiore di Sanità, Rome, Italy.
Fedele
Giorgio
G
Spensieri
Fabiana
F
Palazzo
Raffaella
R
Costantino
Paolo
P
Rappuoli
Rino
R
Ausiello
Clara Maria
CM
D049109:Cell Proliferation; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000166:cytology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology*; D037342:Pertussis Toxin / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
D016207:Cytokines; D020381:Interleukin-17; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases