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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
Robinson, M.J., Sancho, D., Slack, E.C., LeibundGut-Landmann, S. & Sousa, C.R.E. Myeloid C-type lectins in innate immunity. Nat. Immunol. 7, 1258–1265 (2006).
van Vliet, S.J., den Dunnen, J., Gringhuis, S.I., Geijtenbeek, T.B. & van Kooyk, Y. Innate signaling and regulation of dendritic cell immunity. Curr. Opin. Immunol. 19, 435–440 (2007).
Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006).
Underhill, D.M., Rossnagle, E., Lowell, C.A. & Simmons, R.M. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood 106, 2543–2550 (2005).
Geijtenbeek, T.B.H. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).
Gringhuis, S.I. et al. C-type lectin DC-SIGN modulates toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappa B. Immunity 26, 605–616 (2007).
Gross, O. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006).
Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 4, 11–23 (2004).
LeibundGut-Landmann, S. et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 8, 630–638 (2007).
Hohl, T.M., Rivera, A. & Pamer, E.G. Immunity to fungi. Curr. Opin. Immunol. 18, 465–472 (2006).
Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).
Ouaaz, F., Arron, J., Zheng, Y., Choi, Y. & Beg, A.A. Dendritic cell development and survival require distinct NF-κB subunits. Immunity 16, 257–270 (2002).
Rogers, N.C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).
Hayden, M.S. & Ghosh, S. Signaling to NF-κB. Genes Dev. 18, 2195–2224 (2004).
Wellbrock, C., Karasarides, M. & Marais, R. NF-κB and the immune response. Nat. Rev. Mol. Cell Biol. 5, 875–885 (2004).
Chen, L.-F. & Greene, W.C. Shaping the nuclear action of NF-κB. Nat. Rev. Mol. Cell Biol. 5, 392–401 (2004).
Jacque, E., Tchenio, T., Piton, G., Romeo, P.-H. & Baud, V. RelA repression of RelB activity induces selective gene activation downstream of TNF receptors. Proc. Natl. Acad. Sci. USA 102, 14635–14640 (2005).
Yang, F., Tang, E., Guan, K.L. & Wang, C.Y. IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J. Immunol. 170, 5630–5635 (2003).
Tas, S.W. et al. Noncanonical NF-\{kappa\}B signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 110, 1540–1549 (2007).
Saccani, S., Pantano, S. & Natoli, G. Modulation of NF-kappaB activity by exchange of dimers. Mol. Cell 11, 1563–1574 (2003).
Neumann, M. & Naumann, M. Beyond I{kappa}Bs: alternative regulation of NF-\{kappa\}B activity. FASEB J. 21, 2642–2654 (2007).
Yoza, B.K., Hu, J.Y.Q., Cousart, S.L., Forrest, L.M. & McCall, C.E. Induction of RelB participates in endotoxin tolerance. J. Immunol. 177, 4080–4085 (2006).
Liang, M.D., Zhang, Y., McDevit, D., Marecki, S. & Nikolajczyk, B.S. The Interleukin-1beta gene is transcribed from a poised promoter architecture in monocytes. J. Biol. Chem. 281, 9227–9237 (2006).
Zhong, H.H., May, M.J., Jimi, E. & Ghosh, S. The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol. Cell 9, 625–636 (2002).
Chen, L.F. & Greene, W.C. Regulation of distinct biological activities of the NF-kappa B transcription factor complex by acetylation. J. Mol. Med. 81, 549–557 (2003).
Sun, Y., Jiang, X., Chen, S. & Price, B.D. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. FEBS Lett. 580, 4353–4356 (2006).
Saraiva, M. et al. Identification of a macrophage-specific chromatin signature in the IL-10 locus. J. Immunol. 175, 1041–1046 (2005).
Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933–944 (2002).
Manel, N., Unutmaz, D. & Littman, D.R. The differentiation of human TH-17 cells requires transforming growth factor-[beta] and induction of the nuclear receptor ROR[gamma]t. Nat. Immunol. 9, 641–649 (2008).
Volpe, E. et al. A critical function for transforming growth factor-[beta], interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nat. Immunol. 9, 650–657 (2008).
Yang, L. et al. IL-21 and TGF-[bgr] are required for differentiation of human TH17 cells. Nature 454, 350–352 (2008).
Hunter, C.A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat. Rev. Immunol. 5, 521–531 (2005).
Dennehy, K.M. & Brown, G.D. The role of the {beta\}-glucan receptor Dectin-1 in control of fungal infection. J. Leukoc. Biol. 82, 253–258 (2007).
Doyle, S.L. & O'Neill, L.A. Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem. Pharmacol. 72, 1102–1113 (2006).
Zarnegar, B.J. et al. Noncanonical NF-[kappa]B activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 9, 1371–1378 (2008).
Marienfeld, R. et al. RelB forms transcriptionally inactive complexes with RelA/p65. J. Biol. Chem. 278, 19852–19860 (2003).
Carmody, R.J., Ruan, Q.G., Liou, H.C. & Chen, Y.H.H. Essential roles of c-Rel in TLR-induced IL-23 p19 gene expression in dendritic cells. J. Immunol. 178, 186–191 (2007).
Gantner, B.N., Simmons, R.M., Canavera, S.J., Akira, S. & Underhill, D.M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003).
Huffnagle, G.B. & Deepe, G.S. Innate and adaptive determinants of host susceptibility to medically important fungi. Curr. Opin. Microbiol. 6, 344–350 (2003).
Geijtenbeek, T.B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000).
Lackey, K. et al. The discovery of potent cRaf1 kinase inhibitors. Bioorg. Med. Chem. Lett. 10, 223–226 (2000).
Just, I. et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375, 500–503 (1995).
Geahlen, R.L. & McLaughlin, J.L. Piceatannol (3,4,3′,5′-tetrahydroxy-trans-stilbene) is a naturally occurring protein-tyrosine kinase inhibitor. Biochem. Biophys. Res. Commun. 165, 241–245 (1989).
Hanke, J.H. et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 271, 695–701 (1996).
Liu, J., Guan, X., Tamura, T., Ozato, K. & Ma, X. Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. J. Biol. Chem. 279, 55609–55617 (2004).
Faggioli, L., Costanzo, C., Donadelli, M. & Palmieri, M. Activation of the Interleukin-6 promoter by a dominant negative mutant of c-Jun. Biochim. Biophys. Acta 1692, 17–24 (2004).
Chan, C., Li, L., McCall, C.E. & Yoza, B.K. Endotoxin tolerance disrupts chromatin remodeling and NF-\{kappa\}B transactivation at the IL-1β promoter. J. Immunol. 175, 461–468 (2005).
Nakayama, T. et al. Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by Latent Membrane Protein 1 of Epstein-Barr Virus. J. Virol. 78, 1665–1674 (2004).
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.).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 and Supplementary Methods (PDF 1583 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.1692
This article is cited by
-
Targeting CRAF kinase in anti-cancer therapy: progress and opportunities
Molecular Cancer (2023)
-
Receptor basis of biological activity of polysaccharides
Biophysical Reviews (2023)
-
Fungal sensing by dectin-1 directs the non-pathogenic polarization of TH17 cells through balanced type I IFN responses in human DCs
Nature Immunology (2022)
-
Anti-fungal role for type I IFN as dectin-1 triggers non-pathogenic TH17 cell development
Nature Immunology (2022)
-
Mechanism of the fungal-like particles in the inhibition of adipogenesis in 3T3-L1 adipocytes
Scientific Reports (2021)