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

Abstract

The C-type lectin dectin-1 activates the transcription factor NF-κB 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-κB subunits p65 and c-Rel, but also the noncanonical NF-κB subunit RelB. Dectin-1, when stimulated by the β-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-κB 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.

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Figure 1: Dectin-1-mediated signaling activates Raf-1 to control cytokine expression and modulate TLR-mediated signaling.
Figure 2: Syk signaling induces NF-κB activation, whereas Raf-1 induces formation of inactive p65-RelB dimers.
Figure 3: Raf-1 counteracts RelB activation to induce IL-12p40 and IL-1β expression and to limit CCL17 and CCL22 expression.
Figure 4: RelB repression affects NF-κB and RNA polymerase II recruitment differently at the IL12B, IL1B, CCL17 and CCL22 promoters.
Figure 5: Raf-1 signaling affects binding of canonical NF-κB subunits to transcriptional regulatory elements of the IL10, IL12A, IL23A and IL6 genes.
Figure 6: Raf-1-mediated acetylation of p65 regulates IL-10, IL-12p35, IL-23p19, IL-6 and IL-12p40 expression.
Figure 7: Raf-1 signaling controls cytokine production and skews T helper cell differentiation toward TH1.

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Acknowledgements

We thank Y. van Kooyk and R. Mebius for critically reading the manuscript, M. Oudhoff (Academic Centre for Dentistry Amsterdam) for C. albicans and K. Kristiansen (University of Southern Denmark) for the GST-p65 expression plasmid. This work was supported by the Netherlands Organisation for Scientific Research (NWO 917-46-367 to M.L. and NWO 912-04-025 to J.d.D.), the AIDS Foundation (2007036 to M.v.d.V.) and the Dutch Asthma Foundation (3.2.03.39 to S.I.G.).

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S.I.G. and J.d.D. executed most experiments and prepared the manuscript. M.L., M.v.d.V. and B.W. participated in the GST-p65 precipitation, nuclear extract isolation and dectin-1 expression experiments, respectively. S.C.M.B. helped with the T helper cell differentiation assay. S.I.G. and T.B.H.G. designed and interpreted most experiments. T.B.H.G. supervised all aspects of this study, including execution and manuscript preparation.

Note: Supplementary information is available on the Nature Immunology website.

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Correspondence to Teunis B H Geijtenbeek.

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Gringhuis, S., den Dunnen, J., Litjens, M. et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat Immunol 10, 203–213 (2009). https://doi.org/10.1038/ni.1692

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