Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk.
The C-type lectin dectin-1 activates the transcription factor NF-kappaB 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-kappaB subunits p65 and c-Rel, but also the noncanonical NF-kappaB 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-kappaB 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.
Gringhuis
Sonja I
SI
Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, 1007 MC Amsterdam, The Netherlands.
den Dunnen
Jeroen
J
Litjens
Manja
M
van der Vlist
Michiel
M
Wevers
Brigitte
B
Bruijns
Sven C M
SC
Geijtenbeek
Teunis B H
TB
D000107:Acetylation; D002176:Candida albicans / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D009181:Mycoses / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D000099181:Dectin-1
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D000072377:Syk Kinase; D000099181:Dectin-1; C000606896:SYK protein, human