Editors' ChoiceImmunology

Multiple Pathways to Antifungal Immunity

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Science Signaling  27 Jan 2009:
Vol. 2, Issue 55, pp. ec31
DOI: 10.1126/scisignal.255ec31

Dectin-1 is a receptor on dendritic cells that recognizes β-glucan carbohydrates on fungi. Dectin-1 triggers the activation of nuclear factor κB (NF-κB, the p65 and c-Rel subunits) through a canonical pathway involving activation of inhibitor of κB kinase (IKK) complex that requires the kinase Syk. Dectin-1 also elicits Syk-independent signaling that modulates Toll-like receptor (TLR) signaling, and Gringhuis et al. now show that dectin-1 stimulates a noncanonical NF-κB pathway that activates RelB. Costimulation of human dendritic cells with a TLR4 ligand and curdlan (a dectin-1 ligand) triggered changes in the mRNA expression of multiple cytokines, some of which were increased in a Syk-dependent manner and some of which were influenced by the activity of the kinase Raf-1. Raf-1 was activated in cells exposed to curdlan, and this was not prevented by the Syk inhibitor piceatannol. However, induction by curdlan of the mRNA for all of the cytokines was blocked if Syk was inhibited or knocked down with RNAi. In contrast, Raf-1 inhibition or knockdown decreased the abundance of the mRNA encoding interleukin (IL)-10 (IL-10), IL-12p35, IL-12p40, and IL-6 but abolished the increase in the mRNA for IL-1β and increased the production of the mRNA for IL-23p19. Thus, the response to the Raf-1 arm of dectin-1 signaling differed for different cytokines. Dectin-1 stimulated the nuclear translocation and DNA binding of NF-κB subunits p65 and c-Rel, which dimerize with p50, and RelB, which dimerizes with p50. When Syk activity was inhibited, activation of all NF-κB complexes was blocked. In contrast, when Raf-1 activity was inhibited, RelB-p50 activation was enhanced, suggesting that Raf-1 inhibits RelB activity. Exposure of cells to curdlan led to the formation of inactive RelB-p65 complexes, which were associated with Raf-1–mediated phosphorylation of p65. RelB represses the expression of the genes encoding IL-12p40 and IL-1β but stimulates the expression of genes encoding the CC chemokines CCL22 and CCL17. Consequently, inhibition of Raf-1 activity has opposite effects on the regulation of these genes by curdlan. Curdlan stimulation of cells also induced the acetylation of p65, which increases the DNA binding affinity of p65, in a Raf-1–dependent manner. Thus, the Raf-1 arm of dectin-1 signaling tips the balance between the p65 and RelB NF-κB subunits toward active p65, which, in turn, shifts the cytokine response. The effects of the change in NF-κB subunit balance on the various cytokine promoter genes was confirmed by chromatin immunoprecipitation. Dectin-1 signaling through Raf-1 controls the cytokine secretion profile of the dendritic cells to promote differentiation of T helper 1 cells and, when Raf-1 activity was inhibited, curdlan stimulation of dendritic cells in the presence of naïve T cells resulted in the production of T helper 2 cells at the expense of T helper 1 cells.

S. I. Gringhuis, J. den Dunnen, M. Litjens, M. van der Vlist, B. Wevers, S. C. M. Bruijns, T. B. H. Geijtenbeek, Dectin-1 directs T help cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat. Immunol. 10, 203–213 (2009). [PubMed]

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