Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming.
Cholera toxin (CT) is a potent mucosal adjuvant that amplifies B and T cell responses to mucosally co-administered antigens, stimulating predominant Th2-type responses. However, little is known about the mechanism of adjuvanticity of CT and on the influence this toxin may have on Th2 cell development during the priming of an immune response. We analyzed the effect of CT on dendritic cells (DC), which are responsible for the priming of immune responses at the systemic as well as at the mucosal level. We found that CT induces phenotypic and functional maturation of blood monocyte-derived DC. Indeed, CT-treated DC up-regulate expression of HLA-DR molecules, B7. 1 and B7.2 co-stimulatory molecules, and are able to prime naive CD4(+)CD45RA(+) T cells in vitro, driving their polarization towards the Th2 phenotype. Furthermore, CT-matured DC express functional chemokine receptors CCR7 and CXCR4 which may render them responsive to migratory stimuli towards secondary lymphoid organs. Interestingly, the maturation program induced by CT is unique since CT does not induce but rather inhibits cytokine (IL-12p70 and TNF-alpha) and chemokine (RANTES, MIP-1alpha and MIP-1beta) secretion by lipopolysaccharide- or CD40 ligand-activated DC. Our results help to elucidate the mechanism of action of CT as an adjuvant and highlight a new stimulus of bacterial origin that promotes maturation of DC.
Laboratory of Bacteriology and Medical Mycology, Istituto Superiore di Sanità, Rome, Italy.
M C
MC
Gagliardi
F
F
Sallusto
M
M
Marinaro
A
A
Langenkamp
A
A
Lanzavecchia
M T
MT
De Magistris
D000328:Adult; D018122:B7-1 Antigen / Q000096:biosynthesis; D016764:Cell Polarity; D002772:Cholera Toxin / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000187:drug effects; D019707:Receptors, Chemokine / Q000187:drug effects; D018418:Th2 Cells / Q000502:physiology*
D018122:B7-1 Antigen; C515300:CCR1 protein, human; D016207:Cytokines; D006684:HLA-DR Antigens; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D002772:Cholera Toxin