DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production.
The generation of pathogen-specific immune responses is dependent on the signaling capabilities of pathogen-recognition receptors. DC-SIGN is a C-type lectin that mediates capture and internalization of viral, bacterial, and fungal pathogens by myeloid dendritic cells. DC-SIGN-interacting pathogens are thought to modulate dendritic cell maturation by interfering with intracellular signaling from Toll-like receptor molecules. We report that engagement of DC-SIGN by specific antibodies does not promote dendritic cell maturation but induces ERK1/2 and Akt phosphorylation without concomitant p38MAPK activation. DC-SIGN ligation also triggers PLCgamma phosphorylation and transient increases in intracellular calcium in dendritic cells. In agreement with its signaling capabilities, a fraction of DC-SIGN molecules partitions within lipid raft-enriched membrane fractions both in DC-SIGN-transfected and dendritic cells. Moreover, DC-SIGN in dendritic cells coprecipitates with the tyrosine kinases Lyn and Syk. The relevance of the DC-SIGN-initiated signals was demonstrated in monocyte-derived dendritic cells, as DC-SIGN cross-linking synergizes with TNF-alpha for IL-10 release and enhances the production of LPS-induced IL-10. These results demonstrate that DC-SIGN-triggered intracellular signals modulate dendritic cell maturation. Since pathogens stimulate Th2 responses via preferential activation of ERK1/2, these results provide a molecular explanation for the ability of DC-SIGN-interacting pathogens to preferentially evoke Th2-type immune responses.
Caparrós
Esther
E
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, Madrid 28040, Spain.
Munoz
Pilar
P
Sierra-Filardi
Elena
E
Serrano-Gómez
Diego
D
Puig-Kröger
Amaya
A
Rodríguez-Fernández
José L
JL
Mellado
Mario
M
Sancho
Jaime
J
Zubiaur
Mercedes
M
Corbí
Angel L
AL
D015703:Antigens, CD / Q000097:blood / Q000276:immunology; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002460:Cell Line; D003432:Cross-Linking Reagents; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D037181:Lectins, C-Type / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015703:Antigens, CD; D002118:Calcium; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D016207:Cytokines; D016753:Interleukin-10; D037181:Lectins, C-Type; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin