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Adaptive immunity: Rel-ative contributions of Raf and Syk
Functional Glycomics (12 February 2009) | doi:10.1038/fg.2009.6Standfirst
Dectin-1 signals through Syk and Raf-1 to regulate activation of the noncanonical NF-
B pathway and TH cell differentiation in response to fungal infection.
The adaptive immune response is induced by Toll-like receptors and C-type lectins on dendritic cells. These cell-surface receptors bind to infectious agents and trigger cytokine production to stimulate T helper (TH) cell differentiation. The C-type lectin dectin-1 binds to carbohydrate fungal components and stimulates Syk-dependent activation of NF-B subunits. When activated, the NF-B subunits dimerize and translocate to the nucleus to stimulate cytokine transcription. However, the molecular events that link dectin-1 engagement to cytokine production have not yet been fully elucidated. In Nature Immunology, Teunis Geijtenbeek and colleagues now report that dectin-1 engages discrete Syk-dependent and Raf-1-dependent signaling pathways. These two pathways converge at the noncanonical RelB NF-B subunit to fine-tune the cytokine response to fungal infection.
Stimulation of human dendritic cells with the 
-glycan curdlan — a dectin-1 ligand — induced Syk-dependent nuclear translocation of active RelB–p52 NF-B dimers. Small interfering (si)RNA-mediated depletion of RelB blocked production of CCL17 and CCL22 following curdlan stimulation, supporting a role for the noncanonical NF-B pathway in the regulation of gene expression downstream of dectin-1. Interestingly, curdlan also promoted Raf-1-dependent production of interleukin-12p40 (IL-12p40) and IL-1. As RelB is known to block production of IL-12p40, could Raf-1 inhibit RelB to permit production of these cytokines? Indeed, Raf-1 phosphorylated the p65 NF-B subunit, which potentiated the formation of an inactive p65–RelB NF-B dimer and allowed production of IL-12p40 and IL-1. Separately, Raf-1-mediated phosphorylation of p65 also promoted its acetylation, which upregulated p65-stimulated transcription of IL-12p40, IL-12p35 and other cytokines.
How do these pathways contribute to dectin-1-induced TH cell differentiation? Raf-1 signaling downstream of dectin-1 produced cytokines that promote T cell differentiation towards a TH1 and TH-17 response, including IL-12p35, IL-12p40, IL-23p19 and IL-1. In contrast, Raf-1 silencing led to the complete inhibition of IL-12p70, IL-23 and IL-1 protein expression due to the Syk-dependent formation of active RelB–p52 dimers. These observations were extended by treating dendritic cells with Candida albicans, which is recognized by dectin-1. C. albicans activated Raf-1 and induced cytokine production in a Syk-dependent manner. Raf-1 was required for the production of TH1- and TH-17-polarizing cytokines; inhibition of Raf-1 promoted TH2 differentiation.
Thus, dectin-1 signals through Raf-1 and Syk to regulate cytokine production and TH cell differentiation through several distinct mechanisms. A Syk-dependent pathway stimulates the formation of active, noncanonical RelB–p52 dimers, whereas Raf-1 phosphorylates p65 to stimulate the formation of inactive RelB–p65 dimers and additionally promotes p65-dependent transcriptional activity. However, the signals that modulate the incorporation of RelB and p65 into inactive versus active dimers remain to be elucidated.