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Blood, 15 May 2006, Vol. 107, No. 10, pp. 3950-3958.
Prepublished online as a Blood First Edition Paper on January 24, 2006; DOI 10.1182/blood-2005-03-1252.
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IMMUNOBIOLOGY
DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production
Esther Caparrós,
Pilar Munoz,
Elena Sierra-Filardi,
Diego Serrano-Gómez,
Amaya Puig-Kröger,
José L. Rodríguez-Fernández,
Mario Mellado,
Jaime Sancho,
Mercedes Zubiaur, and
Angel L. Corbí
From the Centro de Investigaciones Biológicas and the Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain; and the Instituto de Parasitología y Biomedicina "López-Neyra," Granada, Spain.
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 PLC 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- 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.
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