Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk

The C-type lectin dectin-1 activates the transcription factor NF-kappa B through a Syk kinase-dependent signaling pathway to induce antifungal immunity. Here we show that dectin- 1 expressed on human dendritic cells activates not only the Syk-dependent canonical NF-kappa B subunits p65 and c-Rel, but also the noncanonical NF-kappa B subunit RelB. Dectin-1, when stimulated by the beta-glucan curdlan or by Candida albicans, induced a second signaling pathway mediated by the serine-threonine kinase Raf-1, which integrated with the Syk pathway at the point of NF-kappa B activation. Raf-1 antagonized Syk-induced RelB activation by promoting sequestration of RelB into inactive p65-RelB dimers, thereby altering T helper cell differentiation. Thus, dectin-1 activates two independent signaling pathways, one through Syk and one through Raf-1, to induce immune responses.