Syk-coupled C-type lectins in immunity
2011; Elsevier BV; Volume: 32; Issue: 4 Linguagem: Inglês
10.1016/j.it.2011.01.002
ISSN1471-4981
AutoresAnn M. Kerrigan, Gordon D. Brown,
Tópico(s)Immune Cell Function and Interaction
ResumoThe Syk-coupled C-type lectin receptor Dectin-1 was the first non-Toll like receptor described that could mediate its own intracellular signalling. It was initially identified as important for the innate recognition of and response to fungal pathogens but later studies revealed that it is also involved in triggering adaptive immune responses. It subsequently emerged that Dectin-1 is one of a number of spleen tyrosine kinase-coupled C-type lectin receptors that have been implicated not just in fungal immunity, but also in viral, mycobacterial and helminth infections. Here, we consider the ability of these receptors to trigger different aspects of immunity and highlight their emerging roles in a number of infection scenarios. The Syk-coupled C-type lectin receptor Dectin-1 was the first non-Toll like receptor described that could mediate its own intracellular signalling. It was initially identified as important for the innate recognition of and response to fungal pathogens but later studies revealed that it is also involved in triggering adaptive immune responses. It subsequently emerged that Dectin-1 is one of a number of spleen tyrosine kinase-coupled C-type lectin receptors that have been implicated not just in fungal immunity, but also in viral, mycobacterial and helminth infections. Here, we consider the ability of these receptors to trigger different aspects of immunity and highlight their emerging roles in a number of infection scenarios. The vast body of research in the field of innate immunity over the last 20 years was initially motivated by the prediction that PRRs would recognise evolutionarily conserved molecules on infectious organisms [1Medzhitov R. Approaching the asymptote: 20 years later.Immunity. 2009; 30: 766-775Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar]. The subsequent identification of the Toll-like receptors (TLRs) and other PRR families have seen this theory come of age, and our understanding of innate immunity has increased dramatically during this time. We now know that PRR ligands are not unique to pathogens but can be present on commensal microbes, and found endogenously within the host [2Iwasaki A. Medzhitov R. Regulation of adaptive immunity by the innate immune system.Science. 2010; 327: 291-295Crossref PubMed Scopus (1544) Google Scholar]. Many PRRs that detect microbial infection induce innate immune responses by triggering intracellular signalling, which stimulates expression of genes encoding chemokines, cytokines and other immune mediators; and many of these receptors are involved also in controlling the induction of adaptive immunity [2Iwasaki A. Medzhitov R. Regulation of adaptive immunity by the innate immune system.Science. 2010; 327: 291-295Crossref PubMed Scopus (1544) Google Scholar]. TLRs, nucleotide-oligomerization domain (Nod)-like receptors (NLRs), retinoic acid-inducible gene-1 (RIG-1)-like receptors (RLRs) and some C-type lectin receptors (CLRs) are all PRRs that fit within this latter class of receptor that can trigger both innate and adaptive immune responses. Of particular interest to us are CLRs (Box 1) that signal via spleen tyrosine kinase (Syk) to initiate inflammatory responses and function in both innate and adaptive immunity. Of these receptors, an immune function was first demonstrated for Dectin-1, which functions during fungal infection. Other Syk-coupled CLRs subsequently emerged as having roles in fungal immunity; however, recent studies have associated some of these receptors with mycobacterial, viral and helminth infections. The implication of these receptors in a number of infection types, with functions analogous to those of TLRs in terms of their ability to trigger innate and adaptive immune responses, indicates that these Syk-coupled CLRs have a wide significance in immunity. Dectin-1, Dectin-2, Mincle and possibly CLEC5a are all receptors within this category. In this review we summarise these receptors with a particular emphasis on the points raised above; namely, their emerging roles in different types of infection and their ability to trigger both innate and adaptive immunity.Box 1C-type lectin receptorsThe C-type lectin receptors (CLRs) are a large superfamily of proteins characterised by the presence of one or more C-type lectin-like domains (CTLDs). The superfamily has been divided into 17 groups on the basis of phylogeny and domain organisation [64Zelensky A.N. Gready J.E. The C-type lectin-like domain superfamily.FEBS J. 2005; 272: 6179-6217Crossref PubMed Scopus (1042) Google Scholar]. CLRs were originally described as Ca2+-dependent, carbohydrate-binding proteins; however, many CLRs do not bind carbohydrate ligands and, furthermore, display Ca2+-independent ligand binding. [64Zelensky A.N. Gready J.E. The C-type lectin-like domain superfamily.FEBS J. 2005; 272: 6179-6217Crossref PubMed Scopus (1042) Google Scholar]. Despite the presence of a highly conserved domain, CLRs are functionally diverse and have been implicated in various processes, including cell adhesion, tissue integration and remodelling, platelet activation, complement activation, pathogen recognition, endocytosis and phagocytosis. A prominent role for CLRs in immunity was originally identified in natural killer cells, where they were implicated in controlling natural killer cell function in response to transformed and virally infected cells. The identification of CLRs on myeloid cells raised the possibility that they serve similar functions in controlling cellular activation. Of relevance to this review are myeloid-expressed CLRs belonging to the Group II and V subgroups, many of which have been implicated in immunity and homeostasis. These CLRs are all type II transmembrane receptors with a single extracellular CTLD. In all instances, their functions have been linked to the presence of signalling motifs in their cytoplasmic tails, or their ability to couple with signalling chains, which trigger intracellular signalling through various pathways (for recent reviews on signalling mechanisms, see [3Mocsai A. et al.The SYK tyrosine kinase: a crucial player in diverse biological functions.Nat. Rev. Immunol. 2010; 10: 387-402Crossref PubMed Scopus (885) Google Scholar, 65Geijtenbeek T.B. Gringhuis S.I. Signalling through C-type lectin receptors: shaping immune responses.Nat. Rev. Immunol. 2009; 9: 465-479Crossref PubMed Scopus (948) Google Scholar]). The C-type lectin receptors (CLRs) are a large superfamily of proteins characterised by the presence of one or more C-type lectin-like domains (CTLDs). The superfamily has been divided into 17 groups on the basis of phylogeny and domain organisation [64Zelensky A.N. Gready J.E. The C-type lectin-like domain superfamily.FEBS J. 2005; 272: 6179-6217Crossref PubMed Scopus (1042) Google Scholar]. CLRs were originally described as Ca2+-dependent, carbohydrate-binding proteins; however, many CLRs do not bind carbohydrate ligands and, furthermore, display Ca2+-independent ligand binding. [64Zelensky A.N. Gready J.E. The C-type lectin-like domain superfamily.FEBS J. 2005; 272: 6179-6217Crossref PubMed Scopus (1042) Google Scholar]. Despite the presence of a highly conserved domain, CLRs are functionally diverse and have been implicated in various processes, including cell adhesion, tissue integration and remodelling, platelet activation, complement activation, pathogen recognition, endocytosis and phagocytosis. A prominent role for CLRs in immunity was originally identified in natural killer cells, where they were implicated in controlling natural killer cell function in response to transformed and virally infected cells. The identification of CLRs on myeloid cells raised the possibility that they serve similar functions in controlling cellular activation. Of relevance to this review are myeloid-expressed CLRs belonging to the Group II and V subgroups, many of which have been implicated in immunity and homeostasis. These CLRs are all type II transmembrane receptors with a single extracellular CTLD. In all instances, their functions have been linked to the presence of signalling motifs in their cytoplasmic tails, or their ability to couple with signalling chains, which trigger intracellular signalling through various pathways (for recent reviews on signalling mechanisms, see [3Mocsai A. et al.The SYK tyrosine kinase: a crucial player in diverse biological functions.Nat. Rev. Immunol. 2010; 10: 387-402Crossref PubMed Scopus (885) Google Scholar, 65Geijtenbeek T.B. Gringhuis S.I. Signalling through C-type lectin receptors: shaping immune responses.Nat. Rev. Immunol. 2009; 9: 465-479Crossref PubMed Scopus (948) Google Scholar]). Some Syk-coupled CLRs contain immunoreceptor tyrosine activation (ITAM)-like motifs (also called hemITAMs) in their cytoplasmic tails, whereas others associate with ITAM-containing adaptor molecules, such as Fc receptor γ chain (FcRγ) and DNAX-activating protein of 12 kDa (DAP12). Signalling via ITAMs in myeloid cells is mediated by the recruitment of Syk to phosphorylated tyrosines and several intermediate molecules have been implicated in propagating downstream signalling, which results in various responses including transcriptional regulation through the mitogen-activated protein kinase (MAPK) and nuclear factor of activated T-cells (NFAT) pathways (for a recent review, see [3Mocsai A. et al.The SYK tyrosine kinase: a crucial player in diverse biological functions.Nat. Rev. Immunol. 2010; 10: 387-402Crossref PubMed Scopus (885) Google Scholar]). Syk signalling can also activate nuclear factor (NF)-κB and the formation of a complex involving caspase recruitment domain-containing protein 9 (CARD9), B cell lymphoma 10 (Bcl10) mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) is important for ITAM receptor-mediated triggering of NF-κB and myeloid cell activation [4Hara H. et al.The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors.Nat. Immunol. 2007; 8: 619-629Crossref PubMed Scopus (265) Google Scholar]. Interestingly CARD9 is not involved in the activation of NF-κB downstream of TLRs and Nod2, although it is involved with their activation of MAPKs [4Hara H. et al.The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors.Nat. Immunol. 2007; 8: 619-629Crossref PubMed Scopus (265) Google Scholar, 5Hsu Y.M. et al.The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens.Nat. Immunol. 2007; 8: 198-205Crossref PubMed Scopus (339) Google Scholar]. Dectin-1 (also known as CLEC7a) is expressed predominantly by myeloid cells and recognises β-glucan carbohydrates in the cell walls of a number of fungal species, as well as unidentified mycobacterial ligand(s) (Figure 1) [6Reid D.M. et al.Pattern recognition: recent insights from Dectin-1.Curr. Opin. Immunol. 2009; 21: 30-37Crossref PubMed Scopus (222) Google Scholar]. In response to β-glucans, Dectin-1 triggers intracellular signalling via a cytoplasmic ITAM-like motif. Downstream signalling pathways induce a number of innate immune responses including recruitment of Syk, activation of NF-κB via CARD9, as well as the activation of MAPKs and NFAT [7Gross O. et al.Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.Nature. 2006; 442: 651-656Crossref PubMed Scopus (678) Google Scholar, 8Goodridge H.S. et al.Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells.J. Immunol. 2007; 178: 3107-3115PubMed Google Scholar, 9LeibundGut-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. 2007; 8: 630-638Crossref PubMed Scopus (942) Google Scholar]; although there are reports of differential use of CARD9 by Dectin-1 in mouse macrophages and dendritic cells (DCs) [10Goodridge H.S. et al.Differential use of CARD9 by dectin-1 in macrophages and dendritic cells.J. Immunol. 2009; 182: 1146-1154PubMed Google Scholar]. Furthermore, recent data appear to directly contradict previous reports that immune responses induced by the β-glucan curdlan (a particulate purified β-glucan) are CARD9-dependent [11Bi L. et al.CARD9 mediates dectin-2-induced IκBα kinase ubiquitination leading to activation of NF-κB in response to stimulation by the hyphal form of Candida albicans.J. Biol. Chem. 2010; 285: 25969-25977Crossref PubMed Scopus (98) Google Scholar]. There is also evidence that Dectin-1 can induce Syk-independent signalling through the kinase Raf-1, which converges with the Syk pathway for synergistic activation of p65, as well as regulation of NF-κB-induced cytokine responses [12Gringhuis S.I. et al.Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk.Nat. Immunol. 2009; 10: 203-213Crossref PubMed Scopus (357) Google Scholar]. Given the complexities of Dectin-1 signalling, along with the current ambiguities, further study is required to precisely delineate the downstream pathways in various cell types, particularly the extent of CARD9 involvement. In addition to innate immune responses, Dectin-1 can trigger adaptive immunity, including Th1, Th17 and cytotoxic T-cell responses (for reviews, see [6Reid D.M. et al.Pattern recognition: recent insights from Dectin-1.Curr. Opin. Immunol. 2009; 21: 30-37Crossref PubMed Scopus (222) Google Scholar, 13Kerrigan A.M. Brown G.D. Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs.Immunol. Rev. 2010; 234: 335-352Crossref PubMed Scopus (125) Google Scholar]). Of particular interest is the ability of Dectin-1 to trigger Th17 responses, which are thought to contribute to fungal clearance (Box 2). The exact mechanism linking Dectin-1-Syk-CARD9 signalling with Th17 responses is unclear, but was shown to depend on regulatory T cells and TGF-β [9LeibundGut-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. 2007; 8: 630-638Crossref PubMed Scopus (942) Google Scholar]. Furthermore, the tendency of DCs stimulated via Dectin-1 to produce interleukin (IL)-23 as opposed to IL-12 might contribute to limiting Th1 cell differentiation and consequently reduce negative feedback on Th17 cell differentiation [9LeibundGut-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. 2007; 8: 630-638Crossref PubMed Scopus (942) Google Scholar]. There is evidence suggesting that β-glucans contribute to Candida-specific Th17 responses through a collaborative Dectin-1/TLR2 pathway by inducing the production of prostaglandin E2, which in turn up-regulates the Th17 polarising cytokines IL-6 and IL-23 [14Smeekens S.P. et al.The Candida Th17 response is dependent on mannan- and β-glucan-induced prostaglandin E2.Int. Immunol. 2010; 22: 889-895Crossref PubMed Scopus (63) Google Scholar].Box 2Th17 cells in host defence and autoimmunityT helper cells that were initially characterised by the production of IL-17A (IL-17) have recently emerged as a third distinct subset of effector T cells, the differentiation of which involves cytokines, including TGF-β, IL-1β, IL-6, IL-21 and IL-23, and transcription factors, including retinoic acid receptor-related orphan nuclear receptors (ROR)α and RORγt [66Korn T. et al.IL-17 and Th17 cells.Annu. Rev. Immunol. 2009; 27: 485-517Crossref PubMed Scopus (3859) Google Scholar]. Although the differentiation of this subset has been the focus of intensive research, the precise involvement of cytokines such as IL-23 and TGF-β has presented some controversies, and the relatedness of human and mouse Th17 cells has been questioned.Th17 cells produce a variety of cytokines, such as IL-17, IL-17F, IL-21 and IL-22, which are involved in initiating inflammatory responses. As a result of this activity, Th17 responses have been investigated in terms of their contribution to anti-microbial responses and the induction of autoimmunity. In the case of fungi, there has been some controversy but a number of investigations have shown that Th17 responses are required for protection, at least at mucosal sites [67Conti H.R. Gaffen S.L. Host responses to Candida albicans: Th17 cells and mucosal candidiasis.Microbes Infect. 2010; 12: 518-527Crossref PubMed Scopus (114) Google Scholar]. Indeed, patients with genetic defects resulting in aberrant Th17 responses, including Dectin-1 and CARD9 deficiencies, suffer from chronic mucocutaneous candidiasis and other mucosal fungal infections [24Ferwerda B. et al.Human dectin-1 deficiency and mucocutaneous fungal infections.N. Engl. J. Med. 2009; 361: 1760-1767Crossref PubMed Scopus (610) Google Scholar, 68Glocker E.O. et al.A homozygous CARD9 mutation in a family with susceptibility to fungal infections.N. Engl. J. Med. 2009; 361: 1727-1735Crossref PubMed Scopus (648) Google Scholar]. Th17 responses have also been implicated in anti-bacterial immune responses; however, their role in viral and parasitic infections is less clear [69van de Veerdonk F.L. et al.Th17 responses and host defense against microorganisms: an overview.BMB Rep. 2009; 42: 776-787Crossref PubMed Scopus (89) Google Scholar].Growing evidence has revealed the role of Th17 responses in pathology and autoimmune disease. IL-17, IL-17F and Th17 cells have been implicated in autoimmune diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus and asthma [70Fouser L.A. et al.Th17 cytokines and their emerging roles in inflammation and autoimmunity.Immunol. Rev. 2008; 226: 87-102Crossref PubMed Scopus (184) Google Scholar]. These developments have led to increased efforts in defining the precise involvement of Th17 cells in antimicrobial responses and in the induction of autoimmunity; and in developing strategies to block their pathological effects. T helper cells that were initially characterised by the production of IL-17A (IL-17) have recently emerged as a third distinct subset of effector T cells, the differentiation of which involves cytokines, including TGF-β, IL-1β, IL-6, IL-21 and IL-23, and transcription factors, including retinoic acid receptor-related orphan nuclear receptors (ROR)α and RORγt [66Korn T. et al.IL-17 and Th17 cells.Annu. Rev. Immunol. 2009; 27: 485-517Crossref PubMed Scopus (3859) Google Scholar]. Although the differentiation of this subset has been the focus of intensive research, the precise involvement of cytokines such as IL-23 and TGF-β has presented some controversies, and the relatedness of human and mouse Th17 cells has been questioned. Th17 cells produce a variety of cytokines, such as IL-17, IL-17F, IL-21 and IL-22, which are involved in initiating inflammatory responses. As a result of this activity, Th17 responses have been investigated in terms of their contribution to anti-microbial responses and the induction of autoimmunity. In the case of fungi, there has been some controversy but a number of investigations have shown that Th17 responses are required for protection, at least at mucosal sites [67Conti H.R. Gaffen S.L. Host responses to Candida albicans: Th17 cells and mucosal candidiasis.Microbes Infect. 2010; 12: 518-527Crossref PubMed Scopus (114) Google Scholar]. Indeed, patients with genetic defects resulting in aberrant Th17 responses, including Dectin-1 and CARD9 deficiencies, suffer from chronic mucocutaneous candidiasis and other mucosal fungal infections [24Ferwerda B. et al.Human dectin-1 deficiency and mucocutaneous fungal infections.N. Engl. J. Med. 2009; 361: 1760-1767Crossref PubMed Scopus (610) Google Scholar, 68Glocker E.O. et al.A homozygous CARD9 mutation in a family with susceptibility to fungal infections.N. Engl. J. Med. 2009; 361: 1727-1735Crossref PubMed Scopus (648) Google Scholar]. Th17 responses have also been implicated in anti-bacterial immune responses; however, their role in viral and parasitic infections is less clear [69van de Veerdonk F.L. et al.Th17 responses and host defense against microorganisms: an overview.BMB Rep. 2009; 42: 776-787Crossref PubMed Scopus (89) Google Scholar]. Growing evidence has revealed the role of Th17 responses in pathology and autoimmune disease. IL-17, IL-17F and Th17 cells have been implicated in autoimmune diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus and asthma [70Fouser L.A. et al.Th17 cytokines and their emerging roles in inflammation and autoimmunity.Immunol. Rev. 2008; 226: 87-102Crossref PubMed Scopus (184) Google Scholar]. These developments have led to increased efforts in defining the precise involvement of Th17 cells in antimicrobial responses and in the induction of autoimmunity; and in developing strategies to block their pathological effects. More recent studies demonstrated that Dectin-1 signalling induced by C. albicans and Aspergillus fumigatus is required for activation of the Nlrp3 inflammasome and subsequent IL-1β production [15Hise A.G. et al.An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans.Cell Host Microbe. 2009; 5: 487-497Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 16Gross O. et al.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.Nature. 2009; 459: 433-436Crossref PubMed Scopus (704) Google Scholar, 17Said-Sadier N. et al.Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase.PLoS ONE. 2010; 5: e10008Crossref PubMed Scopus (236) Google Scholar, 18Kankkunen P. et al.(1,3)-β-Glucans activate both dectin-1 and NLRP3 inflammasome in human macrophages.J. Immunol. 2010; 184: 6335-6342Crossref PubMed Scopus (203) Google Scholar], events now known to be crucial for host defence during fungal infection [15Hise A.G. et al.An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans.Cell Host Microbe. 2009; 5: 487-497Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 16Gross O. et al.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.Nature. 2009; 459: 433-436Crossref PubMed Scopus (704) Google Scholar]. Other advances suggest that Dectin-1 signalling mediates the activation of calcineurin, a protein phosphatase required for the candidacidal activity of neutrophils as well as transcriptional responses to C. albicans [19Greenblatt M.B. et al.Calcineurin regulates innate antifungal immunity in neutrophils.J. Exp. Med. 2010; 207: 923-931Crossref PubMed Scopus (119) Google Scholar]. Much of this work has pointed towards an antifungal role for Dectin-1 and indeed loss of this PRR in mice has been shown by different groups to result in increased susceptibility to infections with C. albicans, A. fumigatus and Pneumocystis carinii [15Hise A.G. et al.An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans.Cell Host Microbe. 2009; 5: 487-497Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 20Taylor P.R. et al.Dectin-1 is required for beta-glucan recognition and control of fungal infection.Nat. Immunol. 2007; 8: 31-38Crossref PubMed Scopus (909) Google Scholar, 21Steele C. et al.The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.PLoS Pathog. 2005; 1: e42Crossref PubMed Scopus (419) Google Scholar, 22Werner J.L. et al.Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus.J. Immunol. 2009; 182: 4938-4946Crossref PubMed Scopus (345) Google Scholar, 23Saijo S. et al.Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans.Nat. Immunol. 2007; 8: 39-46Crossref PubMed Scopus (518) Google Scholar]. Furthermore, a polymorphism in humans, which causes loss of cell surface expression of Dectin-1, rendered individuals susceptible to mucocutaneous infections with C. albicans, partly as a consequence of impaired IL-17 production [24Ferwerda B. et al.Human dectin-1 deficiency and mucocutaneous fungal infections.N. Engl. J. Med. 2009; 361: 1760-1767Crossref PubMed Scopus (610) Google Scholar]. With regard to mycobacteria, in vitro studies implied that recognition by Dectin-1 contributed to uptake, respiratory burst induction, cytokine production and the generation of Th1 and Th17 adaptive responses [25Rothfuchs A.G. et al.Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells.J. Immunol. 2007; 179: 3463-3471PubMed Google Scholar, 26Shin D.M. et al.Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1.Cell. Microbiol. 2008; 10: 1608-1621Crossref PubMed Scopus (102) Google Scholar, 27Yadav M. Schorey J.S. The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria.Blood. 2006; 108: 3168-3175Crossref PubMed Scopus (333) Google Scholar, 28Lee H.M. et al.Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes.Cell. Microbiol. 2009; 11: 678-692Crossref PubMed Scopus (64) Google Scholar, 29van de Veerdonk F.L. et al.Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1.J. Leukoc. Biol. 2010; 88: 227-232Crossref PubMed Scopus (86) Google Scholar]. These findings prompted in vivo investigations using an aerosol model of Mycobacterium tuberculosis infection in Dectin-1-deficient mice. This work indicated that Dectin-1 might contribute to disease susceptibility but it plays only a minor role in anti-mycobacterial immunity [30Marakalala M.J. et al.The Syk/CARD9-coupled receptor Dectin-1 is not required for host resistance to Mycobacterium tuberculosis in mice.Microbes Infect. 2010; https://doi.org/10.1016/j.micinf.2010.10.013Crossref PubMed Scopus (43) Google Scholar]. Dectin-2 is expressed on tissue macrophages, some DC subsets and inflammatory monocytes [31Graham L.M. Brown G.D. The Dectin-2 family of C-type lectins in immunity and homeostasis.Cytokine. 2009; 48: 148-155Crossref PubMed Scopus (94) Google Scholar]. Its cytoplasmic tail does not contain defined signalling motifs, but it associates with FcRγ to transduce intracellular signalling [32Sato K. et al.Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses.J. Biol. Chem. 2006; 281: 38854-38866Crossref PubMed Scopus (359) Google Scholar] and the murine form has been shown to bind to several fungi, including C. albicans [32Sato K. et al.Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses.J. Biol. Chem. 2006; 281: 38854-38866Crossref PubMed Scopus (359) Google Scholar, 33McGreal E.P. et al.The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose.Glycobiology. 2006; 16: 422-430Crossref PubMed Scopus (282) Google Scholar, 34Robinson M.J. et al.Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection.J. Exp. Med. 2009; 206: 2037-2051Crossref PubMed Scopus (358) Google Scholar, 35Saijo S. et al.Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans.Immunity. 2010; 32: 681-691Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar] (Figure 1). Recent studies demonstrated that Dectin-2 signalling activated NF-κB through the FcRγ-Syk-CARD9 pathway and MAPKs in a Syk-dependent, CARD9-independent fashion [35Saijo S. et al.Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans.Immunity. 2010; 32: 681-691Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar]. Furthermore, recognition of C. albicans α-mannans by Dectin-2 triggered inflammatory responses and Th17 cell differentiation that was important for host defence [11Bi L. et al.CARD9 mediates dectin-2-induced IκBα kinase ubiquitination leading to activation of NF-κB in response to stimulation by the hyphal form of Candida albicans.J. Biol. Chem. 2010; 285: 25969-25977Crossref PubMed Scopus (98) Google Scholar, 34Robinson M.J. et al.Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection.J. Exp. Med. 2009; 206: 2037-2051Crossref PubMed Scopus (358) Google Scholar, 35Saijo S. et al.Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans.Immunity. 2010; 32: 681-691Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar]. Dectin-2 has been implicated in the recognition of M. tuberculosis (Figure 1) [33McGreal E.P. et al.The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose.Glycobiology. 2006; 16: 422-430Crossref PubMed Scopus (282) Google Scholar], although functional studies evaluating its role in mycobacterial infections have not been reported. Furthermore, murine Dectin-2 is the first Syk-coupled CLR to be associated with helminth infections. Its recognition of soluble components derived from the eggs of Schistosoma mansoni (Figure 1) triggered the Syk-dependent induction of reactive oxygen species and a potassium efflux activating the Nlrp3 inflamm
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