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  • Review Article
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Dectin-1: a signalling non-TLR pattern-recognition receptor

Nature Reviews Immunology volume 6, pages 33–43 (2006)Cite this article

Key Points

  • Dectin-1 is a mainly myeloid-cell-expressed NK-cell-receptor-like C-type lectin that functions as a transmembrane pattern-recognition receptor through its ability to bind β-glucan carbohydrates. Dectin-1 also recognizes an unidentified endogenous ligand on T cells, possibly acting as a co-stimulatory molecule.

  • Following ligand binding, dectin-1 can mediate various cellular responses, including cytokine and chemokine production, the respiratory burst and phagocytosis.

  • Cellular responses are mediated by signalling events initiated from the atypical cytoplasmic immunoreceptor tyrosine-based activation motif of dectin-1 using novel pathways, including the protein spleen tyrosine kinase (SYK) and collaborative signalling with the Toll-like receptors, in a cell-specific manner.

  • Dectin-1 can recognize several fungal pathogens and might play a role in the innate response to these organisms. These pathogens, in turn, might have mechanisms for avoiding recognition by this receptor.

  • Dectin-1 is likely to play a role in the protective effects against infectious and non-infectious diseases exerted by purified soluble β-glucans in vivo, although the mechanisms behind these activities are unclear.

  • On certain genetic backgrounds, dectin-1 can play a central role in the development of β-glucan-induced autoimmune disease and might also contribute to the development of fungal-induced respiratory disorders.

  • The activities of dectin-1 might be representative of other pattern-recognition receptors, especially other myeloid-cell-expressed NK-cell-receptor-like C-type lectins, which have similar signalling motifs in their cytoplasmic tails.

Abstract

Dectin-1 is a natural killer (NK)-cell-receptor-like C-type lectin that is thought to be involved in innate immune responses to fungal pathogens. This transmembrane signalling receptor mediates various cellular functions, from fungal binding, uptake and killing, to inducing the production of cytokines and chemokines. These activities could influence the resultant immune response and can, in certain circumstances, lead to autoimmunity and disease. As I discuss here, understanding the molecular mechanisms behind these functions has revealed new concepts, including collaborative signalling with the Toll-like receptors (TLRs) and the use of spleen tyrosine kinase (SYK), that have implications for the role of other non-TLR pattern-recognition receptors in immunity.

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Figure 1: Methods of pathogen recognition by pattern-recognition receptors (PRRs).
Figure 2: Dectin-1 structure and genomic localization within the myeloid-cell-expressed natural killer (NK)-cell-receptor-like C-type lectin cluster.
Figure 3: Dectin-1-mediated signal transduction.
Figure 4: Dectin-1-mediated cellular responses to fungal β-glucans.

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Acknowledgements

I would like to thank all my colleagues, particularly S. Gordon, for their contributions to the work on dectin-1. I thank S. Gordon, J. Willment, K. Dennehy and E. Sturrock for critically reading the manuscript. I am grateful to the Wellcome Trust and the Edward Jenner Institute for Vaccine Research for financial support. G.D.B. is a Wellcome Trust Senior Research Fellow in biomedical science in South Africa.

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  1. Institute of Infectious Disease and Molecular Medicine, CLS, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa

    Gordon D. Brown

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Supplementary information

Supplementary information S1 (movie)

S1| Phagocytosis of zymosan by cells expressing dectin-1. RAW264.7 cells (a mouse macrophage cell line), which have low levels of endogenous dectin-1 expression, were engineered to express dectin-1 and cultured in the presence of fluorescently-labelled zymosan, before being imaged by immunofluorescent microscopy. Dectin-1-expressing cells can be seen to efficiently recognize and phagocytose zymosan. The movie represents 30 minutes of real-time phagocytosis, speeded up 138-fold. Movies courtesy of S. Heinsbroek (University of Oxford). (AVI 798 kb)

Supplementary information S2 (movie)

S2| Lack of phagocytosis of zymosan by cells expressing low levels dectin-1. RAW264.7 cells (a mouse macrophage cell line), which express low levels of endogenous dectin-1 expression, were cultured in the presence of fluorescently-labelled zymosan and imaged by immunofluorescent microscopy. These cells are unable to efficiently recognize or phagocytose zymosan, unlike RAW264.7 cells engineered to express dectin-1 (see Supplementary information S1 (movie). The movie represents 30 minutes of real-time phagocytosis, speeded up 257-fold. Movies courtesy of S. Heinsbroek (University of Oxford). (AVI 1665 kb)

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DATABASES

Entrez Gene

CR3

dectin-1

LOX1

MICL

NKG2D

SYK

TLR

FURTHER INFORMATION

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Glossary

Pattern-recognition receptor

A receptor that binds to molecular patterns found in pathogens but not mammalian cells. Examples include dectin-1, which binds β-glucans, and Toll-like receptors, which are activated by various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

Pathogen-associated molecular pattern

A molecular pattern that is found in pathogens but not mammalian cells. Examples include β-glucan, which binds dectin-1, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors.

Opsonic recognition

The indirect recognition of microorganisms by specific phagocyte receptors, such as complement receptors, which recognize host serum or tissue-fluid proteins (opsonins), such as complement, that are coated (osponized) on the microbial surface.

Respiratory burst

The activation of a multi-protein enzyme complex, the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which translocates to the phagosome membrane and generates lumenal superoxide anions through the transfer of electrons from NADPH to O2.

Reactive oxygen intermediates

Toxic oxidants, such as hydrogen peroxide and hydroxyl radicals, that are produced by chemical reactions of superoxide anions in the phagosome lumen following the respiratory burst. In neutrophils, hydrogen peroxide can be further converted by myeloperoxidase into the highly toxic oxidant, hypochlorous acid.

Type II transmembrane receptor

Single-pass type II transmembrane receptors have their amino (N) terminus in the cytoplasm and their carboxyl terminus on the cell surface. They have a transmembrane sequence of around 25 hydrophobic amino-acid residues but do not contain a recognizable N-terminal signal sequence, which is required for the secretion of type I receptors, which lie in the opposite orientation in the membrane.

C-type lectin superfamily

A family of proteins that contain one or more C-type lectin-like domain (CTLD), which have been divided into 14 groups based on the organization of their CTLDs. The CTLDs, which were first identified as carbohydrate-recognition domains in Ca2+-dependent lectins, do not all recognize sugars, but are homologous and have a conserved sequence motif that determines the CTLD protein fold.

Immunoreceptor tyrosine-based activation motif

(ITAM). A sequence that is present in the cytoplasmic domains of the invariant chains of various cell-surface immune receptors, such as the T-cell and B-cell receptor, the receptor for IgE (FcεR) and natural-killer-cell activating receptors. Following phosphorylation of their tyrosine residue, ITAMs function as docking sites for SRC homology 2 (SH2)-domain-containing tyrosine kinases and adaptor molecules, thereby facilitating intracellular-signalling cascades.

Alternative macrophage activation

A state of macrophage activation, induced by the T-helper 2 (TH2) cytokines interleukin-4 (IL-4) and IL-13, that is distinct from the classical activation induced by interferon-γ, and which leads to a cellular phenotype involved in humoral immunity and repair.

Tetraspanin

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes, which are defined by several conserved amino acids in the transmembrane domains. Their function is not known clearly, but they seem to interact with many other transmembrane proteins and to form large multimeric protein networks, which might be involved in intracellular signalling.

SKG mice

A BALB/c-derived mouse line that spontaneously develops chronic autoimmune arthritis in non-specific-pathogen-free (non-SPF) conditions. These mice have a point mutation in a SRC homology 2 (SH2) domain of the signal transducer ζ-chain-associated protein kinase of 70 kDa in lymphocytes (ZAP70), resulting in aberrant thymic selection and the production of arthritogenic T cells. Exposure of SKG mice to environmental agents, such as β-glucans, leads to the activation of these T cells and the development of disease.

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Brown, G. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol 6, 33–43 (2006). https://doi.org/10.1038/nri1745

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