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Review
, 21 (1), 30-7

Pattern Recognition: Recent Insights From Dectin-1

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Review

Pattern Recognition: Recent Insights From Dectin-1

Delyth M Reid et al. Curr Opin Immunol.

Abstract

The beta-glucan receptor Dectin-1 is an archetypical non-toll-like pattern recognition receptor expressed predominantly by myeloid cells, which can induce its own intracellular signalling and can mediate a variety of cellular responses, such as cytokine production. Recent identification of the components of these signalling pathways, such as Syk kinase, CARD9 and Raf-1, has provided novel insights into the molecular mechanisms underlying Dectin-1 function. Furthermore, a broader appreciation of the cellular responses mediated by this receptor and the effects of interactions with other receptors, including the TLRs, have greatly furthered our understanding of innate immunity and how this drives the development of adaptive immunity, particularly Th17 responses. Recent studies have highlighted the importance of Dectin-1 in anti-fungal immunity, in both mice and humans, and have suggested a possible involvement of this receptor in the control of mycobacterial infections.

Figures

Figure 1
Figure 1
Schematic representation of the fungal cell wall and downstream cellular responses following engagement of Dectin-1 and TLRs on antigen presenting cells (APC). At the top, the interaction between the yeast cell of a fungus, such as C. albicans, is shown as well as the general architecture of the fungal cell wall, consisting of overlapping layers of highly mannosylated proteins, beta glucans (structure within the insert to the right) and chitin. Antigen presenting cells (APCs), including monocytes, macrophages and DCs, engage fungi and activate host responses via several PRRs including the Toll-like receptors (TLR) and Dectin-1. Dectin-1 is alternatively spliced into two functional isoforms, which differ by the presence or absence of a stalk region (shown in dark blue). Dectin-1 recognises linear or branched 1,3-linked β-glucan, which triggers intracellular signalling through at least two pathways, involving Syk kinase and Raf-1, inducing the production of several cytokines, including IL-10, TNF, IL-2, IL-6 and IL-23. TLRs, on the contrary, which recognise various mannosylated and other fungal cell wall structures, signal through the MyD88-Mal mediated NF-κB pathway and induce the production of both pro and anti-inflammatory cytokines, including TNF, IL-10, IL-12 and TGFβ. Co-stimulation of both receptors can amplify the production of cytokines, including TNF, IL-23, IL-10 and IL-6 while downregulating the production IL-12, influencing the resultant generation of adaptive immunity.
Figure 2
Figure 2
Dectin-1 expressing cells are positioned at portals of pathogen entry and sites of T cell development. Dectin-1 is expressed in the dermal layers of skin and palate (arrowheads) but not on the Langerhans cells. Dectin-1 is also expressed on lung APCs and in the gut, Dectin-1+ cells are located in the villi and Peyer's patches (arrowhead). In lymphoid tissues, Dectin-1+ cells are found in all areas including the germinal centres (small arrowhead in lymph node) and T cell regions around the central arteriole (small arrowhead) in the splenic white pulp. The organised nasal associated lymphoid tissues (O-NALT) demonstrate regional similarities to the lymph node. In the thymus, Dectin-1+ cells appear concentrated at the corticomedullary junctional regions. E: epidermis; D: dermis; PP: Peyers’ patch; B: B cell area; T: T cell area; GC: germinal centre; C: cortex; M: medulla.
Figure 3
Figure 3
Diagrammatic representation of the role of Dectin-1 in anti-Candida immunity in mouse versus man. In mouse, sensing of Candia albicans by Dectin-1 on phagocytes (monocytes, macrophages, dendritic cells and neutrophils) results in the ingestion and killing of these organisms, and the induction of early inflammatory cytokines and chemokines. This results in cellular activation and recruitment of immune cells to the site of infection, and stimulates the development of adaptive immunity, including CD4+ and CD8+ T cell responses. In mice, defects in these responses, caused by deficiency of Dectin-1, result in susceptibility to systemic and mucosal candidiasis. In humans, Dectin-1 appears to function similarly; however, phagocytes deficient in Dectin-1 only show defects in cytokine responses, suggesting that other receptors, such as the mannose receptor, are responsible for fungal uptake and killing. The differences in the use of Dectin-1 presumably explain the susceptibility to mucocutaneous, but not systemic, candidiasis that is observed in humans with defects in this receptor.

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References

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