The C-type lectins are a superfamily of proteins that recognize a broad repertoire of ligands and that regulate a diverse range of physiological functions. Most research attention has focused on the ability of C-type lectins to function in innate and adaptive antimicrobial immune responses, but these proteins are increasingly being recognized to have a major role in autoimmune diseases and to contribute to many other aspects of multicellular existence. Defects in these molecules lead to developmental and physiological abnormalities, as well as altered susceptibility to infectious and non-infectious diseases. In this Review, we present an overview of the roles of C-type lectins in immunity and homeostasis, with an emphasis on the most exciting recent discoveries.
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Zelensky, A. N. & Gready, J. E. The C-type lectin-like domain superfamily. FEBS J. 272, 6179–6217 (2005).
Weis, W. I., Taylor, M. E. & Drickamer, K. The C-type lectin superfamily in the immune system. Immunol. Rev. 163, 19–34 (1998).
Ivetic, A. Signals regulating L-selectin-dependent leucocyte adhesion and transmigration. Int. J. Biochem. Cell Biol. 45, 550–555 (2013).
Lafouresse, F. et al. L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo. Blood 126, 1336–1345 (2015).
Poulin, L. F. et al. DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues. Blood 119, 6052–6062 (2012).
Villani, A. C. et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356, eaah4573 (2017).
Schraml, B. U. et al. Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage. Cell 154, 843–858 (2013).
Sancho, D. & Reis e Sousa, C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu. Rev. Immunol. 30, 491–529 (2012).
Cibrian, D. & Sanchez-Madrid, F. CD69: from activation marker to metabolic gatekeeper. Eur. J. Immunol. 47, 946–953 (2017).
Willment, J. A. et al. The human beta-glucan receptor is widely expressed and functionally equivalent to murine dectin-1 on primary cells. Eur. J. Immunol. 35, 1539–1547 (2005).
Whitsett, J. A. & Weaver, T. E. Alveolar development and disease. Am. J. Respir. Cell. Mol. Biol. 53, 1–7 (2015).
Kang, I. et al. Versican deficiency significantly reduces lung inflammatory response induced by polyinosine-polycytidylic acid stimulation. J. Biol. Chem. 292, 51–63 (2017).
Tanisawa, K. et al. Exome-wide association study identifies CLEC3B missense variant p. S106G as being associated with extreme longevity in East Asian populations. J. Gerontol. A. Biol. Sci. Med. Sci. 72, 309–318 (2017).
Yue, R., Shen, B. & Morrison, S. J. Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton. eLife 5, e18782 (2016). This paper defines a key role for the poorly described tetranectin subfamily member CLEC11A as a growth factor that is required to promote bone formation from mesenchymal progenitors.
Fedeles, S. V., Gallagher, A. R. & Somlo, S. Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol. Med. 20, 251–260 (2014).
Lowe, K. L. et al. Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development. Blood 125, 3769–3777 (2015).
Haining, E. J. et al. CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 130, 2224–2228 (2017).
Suzuki-Inoue, K., Osada, M. & Ozaki, Y. Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood. J. Thromb. Haemost. 15, 219–229 (2017).
Acton, S. E. et al. Dendritic cells control fibroblastic reticular network tension and lymph node expansion. Nature 514, 498–502 (2014).
Astarita, J. L. et al. The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat. Immunol. 16, 75–84 (2015). References 19 and 20 reveal the importance of CLEC2 expression by DCs and its interactions with podoplanin expressed by fibroblastic reticular cells for facilitating the rapid lymph node expansion that is required to initiate adaptive immune responses.
Mi, Y. et al. Functional consequences of mannose and asialoglycoprotein receptor ablation. J. Biol. Chem. 291, 18700–18717 (2016).
Burley, K. et al. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood 128, 1879–1883 (2016).
Nakamura-Ishizu, A., Takubo, K., Kobayashi, H., Suzuki-Inoue, K. & Suda, T. CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. J. Exp. Med. 212, 2133–2146 (2015).
Shahrour, M. A. et al. Hypomyelinating leukodystrophy associated with a deleterious mutation in the ATRN gene. Neurogenetics 18, 135–139 (2017).
Friedrich, D. et al. Does human attractin have DP4 activity? Biol. Chem. 388, 155–162 (2007).
Martin, M. & Blom, A. M. Complement in removal of the dead — balancing inflammation. Immunol. Rev. 274, 218–232 (2016).
Sancho, D. & Reis e Sousa, C. Sensing of cell death by myeloid C-type lectin receptors. Curr. Opin. Immunol. 25, 46–52 (2013).
Neumann, K. et al. Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunity 40, 389–399 (2014). This study provides one of the first insights into the endogenous ligands of inhibitory C-type lectins and the importance of these receptors in regulating inflammatory responses.
Hanc, P. et al. Structure of the complex of F-actin and DNGR-1, a C-type lectin receptor involved in dendritic cell cross-presentation of dead cell-associated antigens. Immunity 42, 839–849 (2015).
Nagata, M. et al. Intracellular metabolite beta-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity. Proc. Natl Acad. Sci. USA 114, E3285–E3294 (2017).
Zhou, H. et al. IRAKM-Mincle axis links cell death to inflammation: pathophysiological implications for chronic alcoholic liver disease. Hepatology 64, 1978–1993 (2016).
Greco, S. H. et al. Mincle signaling promotes Con A hepatitis. J. Immunol. 197, 2816–2827 (2016).
Tanaka, M. et al. Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. Nat. Commun. 5, 4982 (2014).
Arumugam, T. V. et al. An atypical role for the myeloid receptor Mincle in central nervous system injury. J. Cereb. Blood Flow Metab. 37, 2098–2111 (2017).
Seifert, L. et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532, 245–249 (2016). This study provides a key observation linking a DAMP released by cancer cells, SAP130, with activation of the C-type lectin mincle, which promotes immunosuppressive macrophage responses that favour oncogenesis.
Kostarnoy, A. V. et al. Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate. Proc. Natl Acad. Sci. USA 114, E2758–E2765 (2017). This manuscript exemplifies how recognition of DAMPs by C-type lectins can trigger inappropriate responses that promote allergic inflammation.
Hanc, P. et al. A pH- and ionic strength-dependent conformational change in the neck region regulates DNGR-1 function in dendritic cells. EMBO J. 35, 2484–2497 (2016).
Cao, L., Shi, X., Chang, H., Zhang, Q. & He, Y. pH-dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205. Proc. Natl Acad. Sci. USA 112, 7237–7242 (2015).
Ding, D., Yao, Y., Zhang, S., Su, C. & Zhang, Y. C-type lectins facilitate tumor metastasis. Oncol. Lett. 13, 13–21 (2017).
Shirai, T. et al. C-Type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice. J. Thromb. Haemost. 15, 513–525 (2017).
Ku, A. W. et al. Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes. eLife 5, e17375 (2016).
Daley, D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23, 556–567 (2017).
Shifrin, N., Raulet, D. H. & Ardolino, M. NK cell self tolerance, responsiveness and missing self recognition. Semin. Immunol. 26, 138–144 (2014).
Lanier, L. L. NKG2D receptor and its ligands in host defense. Cancer Immunol. Res. 3, 575–582 (2015).
Deng, W. et al. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348, 136–139 (2015). This is the first report showing that an NKG2D ligand, ULBP1, shed from cancerous cells can activate, rather than repress, the protective functions of NK cells.
Crane, C. A. et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc. Natl Acad. Sci. USA 111, 12823–12828 (2014).
Kimura, Y. et al. The innate immune receptor dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis. Proc. Natl Acad. Sci. USA 113, 14097–14102 (2016).
Seifert, L. et al. Dectin-1 regulates hepatic fibrosis and hepatocarcinogenesis by suppressing TLR4 signaling pathways. Cell Rep. 13, 1909–1921 (2015).
Chiba, S. et al. Recognition of tumor cells by dectin-1 orchestrates innate immune cells for anti-tumor responses. eLife 3, e04177 (2014).This paper describes how myeloid cell-expressed dectin 1 recognizes tumour-associated carbohydrates, inducing an IRF5-dependent transcriptional response that leads to NK cell activation and antitumour immune responses.
Albeituni, S. H. et al. Yeast-derived particulate beta-glucan treatment subverts the suppression of myeloid-derived suppressor cells (MDSC) by inducing polymorphonuclear MDSC apoptosis and monocytic MDSC differentiation to APC in cancer. J. Immunol. 196, 2167–2180 (2016).
Zhao, Y. et al. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat. Commun. 7, 12368 (2016).
Streng-Ouwehand, I. et al. Glycan modification of antigen alters its intracellular routing in dendritic cells, promoting priming of T cells. eLife 5, e11765 (2016).
Geijtenbeek, T. B. & Gringhuis, S. I. C-type lectin receptors in the control of T helper cell differentiation. Nat. Rev. Immunol. 16, 433–448 (2016). This Review covers the effect of C-type lectins on adaptive immunity, as well as their intracellular signalling pathways.
Joo, H. et al. C-Type lectin-like receptor LOX-1 promotes dendritic cell-mediated class-switched B cell responses. Immunity 41, 592–604 (2014).
Dambuza, I. M. & Brown, G. D. C-type lectins in immunity: recent developments. Curr. Opin. Immunol. 32C, 21–27 (2015).
Mansour, M. K. et al. Dectin-1 activation controls maturation of beta-1,3-glucan-containing phagosomes. J. Biol. Chem. 288, 16043–16054 (2013).
Drummond, R. A., Gaffen, S. L., Hise, A. G. & Brown, G. D. Innate defense against fungal pathogens. Cold Spring Harb. Perspect. Med. 5, a019620 (2014).
Lee, M. J. et al. Phosphoinositide 3-kinase delta regulates dectin-2 signaling and the generation of Th2 and Th17 immunity. J. Immunol. 197, 278–287 (2016).
Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).
Li, S. S. et al. The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients. Cell Host Microbe 14, 387–397 (2013).
Ali, M. F., Driscoll, C. B., Walters, P. R., Limper, A. H. & Carmona, E. M. β-Glucan-activated human B lymphocytes participate in innate immune responses by releasing proinflammatory cytokines and stimulating neutrophil chemotaxis. J. Immunol. 195, 5318–5326 (2015).
Drummond, R. A. & Lionakis, M. S. Mechanistic insights into the role of C-type lectin receptor/CARD9 signaling in human antifungal immunity. Front. Cell. Infect. Microbiol. 6, 39 (2016).
Wirnsberger, G. et al. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nat. Med. 22, 915–923 (2016).
Xiao, Y. et al. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nat. Med. 22, 906–914 (2016).
Zhu, L. L. et al. E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. J. Exp. Med. 213, 1555–1570 (2016).
Zhao, X. et al. JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression. Nat. Med. 23, 337–346 (2017). References 64–66 describe CBLB as a key negative regulator of C-type lectin-mediated signalling during fungal infection, making it an attractive target for the development of novel antifungal therapeutics.
Roth, S. et al. Vav proteins are key regulators of Card9 signaling for innate antifungal immunity. Cell Rep. 17, 2572–2583 (2016).
Cao, Z. et al. Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. Immunity 43, 715–726 (2015).
Iborra, S. et al. Leishmania uses Mincle to target an inhibitory ITAM signaling pathway in dendritic cells that dampens adaptive immunity to infection. Immunity 45, 788–801 (2016).
Blanco-Menendez, N. et al. SHIP-1 couples to the dectin-1 hemITAM and selectively modulates reactive oxygen species production in dendritic cells in response to Candida albicans. J. Immunol. 195, 4466–4478 (2015).
Deng, Z. et al. Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses. Nat. Immunol. 16, 642–652 (2015). This paper unexpectedly shows that the phosphatase SHP2 functions as an essential scaffold facilitating SYK recruitment and C-type lectin-mediated intracellular signalling.
Rieber, N. et al. Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells. Cell Host Microbe 17, 507–514 (2015).
Drummond, R. A. et al. CD4+ T-cell survival in the GI tract requires dectin-1 during fungal infection. Mucosal Immunol. 9, 492–502 (2016).
Iliev, I. D. et al. Interactions between commensal fungi and the C-type lectin receptor dectin-1 influence colitis. Science 336, 1314–1317 (2012).
Tang, C. et al. Inhibition of dectin-1 signaling ameliorates colitis by inducing Lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 18, 183–197 (2015).
Yang, A. M. et al. Intestinal fungi contribute to development of alcoholic liver disease. J. Clin. Invest. 127, 2829–2841 (2017).
Choteau, L. et al. Role of mannose-binding lectin in intestinal homeostasis and fungal elimination. Mucosal Immunol. 9, 767–776 (2016).
Kashem, S. W. et al. Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 42, 356–366 (2015).
Branzk, N. et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat. Immunol. 15, 1017–1025 (2014).
Loures, F. V. et al. Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps. PLoS Pathog. 11, e1004643 (2015).
Ter Horst, R. et al. Host and environmental factors influencing individual human cytokine responses. Cell 167, 1111–1124.e3 (2016).
Schonherr, F. A. et al. The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity. Mucosal Immunol. 10, 1335–1350 (2017).
Wuthrich, M. et al. Fonsecaea pedrosoi-induced Th17-cell differentiation in mice is fostered by dectin-2 and suppressed by Mincle recognition. Eur. J. Immunol. 45, 2542–2552 (2015).
Wevers, B. A. et al. Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity. Cell Host Microbe 15, 494–505 (2014).
Garfoot, A. L., Shen, Q., Wuthrich, M., Klein, B. S. & Rappleye, C. A. The Eng1 beta-glucanase enhances histoplasma virulence by reducing beta-glucan exposure. mBio 7, e01388–01315 (2016).
Goyal, S., Klassert, T. E. & Slevogt, H. C-type lectin receptors in tuberculosis: what we know. Med. Microbiol. Immunol. 205, 513–535 (2016).
Yonekawa, A. et al. Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria. Immunity 41, 402–413 (2014).
Toyonaga, K. et al. C-type lectin receptor DCAR recognizes mycobacterial phosphatidyl-inositol mannosides to promote a Th1 response during infection. Immunity 45, 1245–1257 (2016).
Ostrop, J. et al. Contribution of MINCLE-SYK signaling to activation of primary human APCs by mycobacterial cord factor and the novel adjuvant TDB. J. Immunol. 195, 2417–2428 (2015).
Tientcheu, L. D. et al. Immunological consequences of strain variation within the Mycobacterium tuberculosis complex. Eur. J. Immunol. 47, 432–445 (2017).
Wilson, G. J. et al. The C-type lectin receptor CLECSF8/CLEC4D is a key component of anti-mycobacterial immunity. Cell Host Microbe 17, 252–259 (2015). This paper describes MCL as the first non-redundant PRR required for the control of mycobacterial infection in both mice and humans.
Dorhoi, A. et al. The adaptor molecule CARD9 is essential for tuberculosis control. J. Exp. Med. 207, 777–792 (2010).
Troegeler, A. et al. C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells. Proc. Natl Acad. Sci. USA 114, E540–E549 (2017).
Behler-Janbeck, F. et al. C-type lectin Mincle recognizes glucosyl-diacylglycerol of Streptococcus pneumoniae and plays a protective role in pneumococcal pneumonia. PLoS Pathog. 12, e1006038 (2016).
Sharma, A., Steichen, A. L., Jondle, C. N., Mishra, B. B. & Sharma, J. Protective role of Mincle in bacterial pneumonia by regulation of neutrophil mediated phagocytosis and extracellular trap formation. J. Infect. Dis. 209, 1837–1846 (2014).
Chen, S. T. et al. CLEC5A is a critical receptor in innate immunity against Listeria infection. Nat. Commun. 8, 299 (2017).
Hashimoto, J. et al. Surfactant protein A inhibits growth and adherence of uropathogenic Escherichia coli to protect the bladder from infection. J. Immunol. 198, 2898–2905 (2017).
Bonder, M. J. et al. The effect of host genetics on the gut microbiome. Nat. Genet. 48, 1407–1412 (2016).
Lightfoot, Y. L. et al. SIGNR3-dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis. EMBO J. 34, 881–895 (2015).
Gringhuis, S. I., Kaptein, T. M., Wevers, B. A., Mesman, A. W. & Geijtenbeek, T. B. Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKepsilon- and CYLD-dependent Bcl3 activation. Nat. Commun. 5, 3898 (2014).
Mukherjee, S. et al. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505, 103–107 (2014).
Greene, T. T. et al. A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression. eLife 5, e14749 (2016).
Schmiedel, D. & Mandelboim, O. Disarming cellular alarm systems-manipulation of stress-induced NKG2D ligands by human herpesviruses. Front. Immunol. 8, 390 (2017).
Ribeiro, C. M. et al. Receptor usage dictates HIV-1 restriction by human TRIM5alpha in dendritic cell subsets. Nature 540, 448–452 (2016). This paper shows how langerin, but not DC-SIGN, uses a TRIM5α-mediated autophagy pathway to target HIV for lysosomal degradation in human Langerhans cells.
van den Berg, L. M. et al. Langerhans cell-dendritic cell cross-talk via langerin and hyaluronic acid mediates antigen transfer and cross-presentation of HIV-1. J. Immunol. 195, 1763–1773 (2015).
Iborra, S. et al. The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice. J. Clin. Invest. 122, 1628–1643 (2012).
Zelenay, S. et al. The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J. Clin. Invest. 122, 1615–1627 (2012).
Monteiro, J. T. & Lepenies, B. Myeloid C-type lectin receptors in viral recognition and antiviral immunity. Viruses 9, E59 (2017).
Mesman, A. W. et al. Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases. Cell Host Microbe 16, 31–42 (2014).
Chen, S. T. et al. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453, 672–676 (2008).
Teng, O. et al. CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza virus pathogenicity in vivo. J. Virol. 91, e01813–01816 (2017).
Zhao, D. et al. The myeloid LSECtin is a DAP12-coupled receptor that is crucial for inflammatory response induced by Ebola virus glycoprotein. PLoS Pathog. 12, e1005487 (2016).
Huang, Y. L. et al. CLEC5A is critical for dengue virus-induced osteoclast activation and bone homeostasis. J. Mol. Med. 94, 1025–1037 (2016).
Jaeger, M., Stappers, M. H., Joosten, L. A., Gyssens, I. C. & Netea, M. G. Genetic variation in pattern recognition receptors: functional consequences and susceptibility to infectious disease. Future Microbiol. 10, 989–1008 (2015).
Vazquez-Mendoza, A., Carrero, J. C. & Rodriguez-Sosa, M. Parasitic infections: a role for C-type lectins receptors. Biomed. Res. Int. 2013, 456352 (2013).
Cestari, I., Evans-Osses, I., Schlapbach, L. J., de Messias-Reason, I. & Ramirez, M. I. Mechanisms of complement lectin pathway activation and resistance by trypanosomatid parasites. Mol. Immunol. 53, 328–334 (2013).
Vazquez, A. et al. Mouse macrophage galactose-type lectin (mMGL) is critical for host resistance against Trypanosoma cruzi infection. Int. J. Biol. Sci. 10, 909–920 (2014).
Thawer, S. et al. Surfactant protein-D is essential for immunity to helminth infection. PLoS Pathog. 12, e1005461 (2016). This manuscript highlights the importance of the collectin SP-D in protective innate immune responses in the lungs during infection with parasitic worms.
Caliz, R. et al. Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis. PLoS ONE 8, e72732 (2013).
Hanyecz, A. et al. Proteoglycan aggrecan conducting T cell activation and apoptosis in a murine model of rheumatoid arthritis. Biomed. Res. Int. 2014, 942148 (2014).
Markovics, A. et al. Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis. PLoS ONE 11, e0160284 (2016).
Epp Boschmann, S. et al. Mannose-binding lectin polymorphisms and rheumatoid arthritis: a short review and meta-analysis. Mol. Immunol. 69, 77–85 (2016).
Guo, J. et al. A replication study confirms the association of dendritic cell immunoreceptor (DCIR) polymorphisms with ACPA-negative RA in a large Asian cohort. PLoS ONE 7, e41228 (2012).
Fujikado, N. et al. Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat. Med. 14, 176–180 (2008).
Maruhashi, T. et al. DCIR maintains bone homeostasis by regulating IFN-gamma production in T cells. J. Immunol. 194, 5681–5691 (2015).
Redelinghuys, P. et al. MICL controls inflammation in rheumatoid arthritis. Ann. Rheum. Dis. 75, 1386–1391 (2016).
Joyce-Shaikh, B. et al. Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis. J. Exp. Med. 207, 579–589 (2010).
Hashimoto, K., Oda, Y., Nakamura, F., Kakinoki, R. & Akagi, M. Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis. Eur. J. Histochem. 61, 2762 (2017).
Chen, D. Y. et al. A potential role of myeloid DAP12-associating lectin (MDL)-1 in the regulation of inflammation in rheumatoid arthritis patients. PLoS ONE 9, e86105 (2014).
Ishikawa, M. et al. Plasma sLOX-1 is a potent biomarker of clinical remission and disease activity in patients with seropositive RA. Mod. Rheumatol 26, 696–701 (2016).
Andersson, A. K. et al. Blockade of NKG2D ameliorates disease in mice with collagen-induced arthritis: a potential pathogenic role in chronic inflammatory arthritis. Arthritis Rheum. 63, 2617–2629 (2011).
Mariaselvam, C. M. et al. Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis. Clin. Exp. Immunol. 187, 369–375 (2017).
Soleimanpour, S. A. et al. The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157, 1577–1590 (2014).
Schuster, C. et al. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42, 942–952 (2015). Variation in CLEC16A is associated with multiple autoimmune diseases; this study shows that this probably results from the role of CLEC16A in thymic epithelial cell autophagy, which affects thymocyte selection.
Li, J. et al. Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. Nat. Commun. 6, 6804 (2015).
Bronson, P. G. et al. Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nat. Genet. 48, 1425–1429 (2016).
Axelgaard, E., Ostergaard, J. A., Thiel, S. & Hansen, T. K. Diabetes is associated with increased autoreactivity of mannan-binding lectin. J. Diabetes Res. 2017, 6368780 (2017).
Yan, M., Mehta, J. L., Zhang, W. & Hu, C. LOX-1, oxidative stress and inflammation: a novel mechanism for diabetic cardiovascular complications. Cardiovasc. Drugs Ther. 25, 451–459 (2011).
Zou, X. Z. et al. Involvement of epithelial-mesenchymal transition afforded by activation of LOX-1/ TGF-beta1/KLF6 signaling pathway in diabetic pulmonary fibrosis. Pulm. Pharmacol. Ther. 44, 70–77 (2017).
Karumuthil-Melethil, S., Perez, N., Li, R. & Vasu, C. Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. J. Immunol. 181, 8323–8334 (2008).
Yoshimoto, R. et al. The discovery of LOX-1, its ligands and clinical significance. Cardiovasc. Drugs Ther. 25, 379–391 (2011).
Rizzacasa, B. et al. LOX-1 and its splice variants: a new challenge for atherosclerosis and cancer-targeted therapies. Int. J. Mol. Sci. 18, E290 (2017).
Thakkar, S. et al. Structure-based design targeted at LOX-1, a receptor for oxidized low-density lipoprotein. Sci. Rep. 5, 16740 (2015).
Biocca, S. et al. Molecular mechanism of statin-mediated LOX-1 inhibition. Cell Cycle 14, 1583–1595 (2015).
Wight, T. N., Kinsella, M. G., Evanko, S. P., Potter-Perigo, S. & Merrilees, M. J. Versican and the regulation of cell phenotype in disease. Biochim. Biophys. Acta 1840, 2441–2451 (2014).
Sorensen, G. L. et al. Surfactant protein D is proatherogenic in mice. Am. J. Physiol. Heart Circ. Physiol. 290, H2286–H2294 (2006).
Hirano, Y. et al. Surfactant protein-D deficiency suppresses systemic inflammation and reduces atherosclerosis in ApoE knockout mice. Cardiovasc. Res. 113, 1208–1218 (2017).
Sorensen, G. L. et al. Association between the surfactant protein D (SFTPD) gene and subclinical carotid artery atherosclerosis. Atherosclerosis 246, 7–12 (2016).
Haddad, Y. et al. The dendritic cell receptor DNGR-1 promotes the development of atherosclerosis in mice. Circ. Res. 121, 234–243 (2017).
Kiyotake, R. et al. Human Mincle binds to cholesterol crystals and triggers innate immune responses. J. Biol. Chem. 290, 25322–25332 (2015).
Clement, M. et al. Necrotic cell sensor Clec4e promotes a proatherogenic macrophage phenotype through activation of the unfolded protein response. Circulation 134, 1039–1051 (2016).
Salazar, F., Sewell, H. F., Shakib, F. & Ghaemmaghami, A. M. The role of lectins in allergic sensitization and allergic disease. J. Allergy Clin. Immunol. 132, 27–36 (2013).
Higashino-Kameda, M. et al. A critical role of dectin-1 in hypersensitivity pneumonitis. Inflamm. Res. 65, 235–244 (2016).
Ito, T. et al. Dectin-1 plays an important role in house dust mite-induced allergic airway inflammation through the activation of CD11b+ dendritic cells. J. Immunol. 198, 61–70 (2017).
Overton, N. L., Simpson, A., Bowyer, P. & Denning, D. W. Genetic susceptibility to severe asthma with fungal sensitization. Int. J. Immunogenet. 44, 93–106 (2017).
Mackay, R. M. et al. Airway surfactant protein D deficiency in adults with severe asthma. Chest 149, 1165–1172 (2016).
Kamalakannan, M., Chang, L. M., Grishina, G., Sampson, H. A. & Masilamani, M. Identification and characterization of DC-SIGN-binding glycoproteins in allergenic foods. Allergy 71, 1145–1155 (2016).
Salazar, F. et al. The mannose receptor negatively modulates the Toll-like receptor 4-aryl hydrocarbon receptor-indoleamine 2,3-dioxygenase axis in dendritic cells affecting T helper cell polarization. J. Allergy Clin. Immunol. 137, 1841–1851.e2 (2016).
Ito, T. et al. IL-22 induces Reg3gamma and inhibits allergic inflammation in house dust mite-induced asthma models. J. Exp. Med. 214, 3037–3050 (2017).
Do, D. C. et al. N-Glycan in cockroach allergen regulates human basophil function. Immun. Inflamm Dis. 5, 386–399 (2017).
Acharya, K. R. & Ackerman, S. J. Eosinophil granule proteins: form and function. J. Biol. Chem. 289, 17406–17415 (2014).
Cibrian, D. et al. CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat. Immunol. 17, 985–996 (2016).
Uto, T. et al. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity. Nat. Commun. 7, 11273 (2016).
Akatsu, C. et al. CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP. J. Exp. Med. 213, 2691–2706 (2016).
Lee, E. J. et al. Mincle activation and the Syk/Card9 signaling axis are central to the development of autoimmune disease of the eye. J. Immunol. 196, 3148–3158 (2016).
Stoppelkamp, S. et al. Murine pattern recognition receptor dectin-1 is essential in the development of experimental autoimmune uveoretinitis. Mol. Immunol. 67, 398–406 (2015).
Quatrini, L. et al. Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells. Sci. Signal. 8, ra108 (2015).
Redelinghuys, P. & Brown, G. D. Inhibitory C-type lectin receptors in myeloid cells. Immunol. Lett. 136, 1–12 (2011).
Hsu, Y. Y. et al. Thrombomodulin promotes focal adhesion kinase activation and contributes to angiogenesis by binding to fibronectin. Oncotarget 7, 68122–68139 (2016).
Asano, K. et al. Secretion of inflammatory factors from chondrocytes by layilin signaling. Biochem. Biophys. Res. Commun. 452, 85–90 (2014).
Trudel, M., Yao, Q. & Qian, F. The role of G-protein-coupled receptor proteolysis site cleavage of polycystin-1 in renal physiology and polycystic kidney disease. Cells 5, 3 (2016).
Kato, Y. et al. Targeting antigen to Clec9A primes follicular Th cell memory responses capable of robust recall. J. Immunol. 195, 1006–1014 (2015).
van der Meer, J. W., Joosten, L. A., Riksen, N. & Netea, M. G. Trained immunity: a smart way to enhance innate immune defence. Mol. Immunol. 68, 40–44 (2015).
The authors thank the Wellcome Trust, the UK Medical Research Council (MRC), the MRC Centre for Medical Mycology at the University of Aberdeen and Arthritis Research UK for financial support. The authors apologize to colleagues whose many valuable contributions could not be cited owing to space constraints.
Nature Reviews Immunology thanks S. Gringhuis, J. Ruland and D. Sancho for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Imperial College London C-type Lectins website: http://www.imperial.ac.uk/research/animallectins/ctld/classes/C-type1.html
Proteins that are heavily glycosylated, normally with one or more covalently attached glycosaminoglycans. They are found in the extracellular matrix, in connective tissue and on the surface of cells.
- Autosomal dominant polycystic kidney disease
One of the most common monogenic diseases found in humans; it is characterized by structurally abnormal renal tubules that form fluid-filled cysts.
- Fibroblastic reticular cells
(FRCs). Myofibroblast stromal cells of mesenchymal origin found in lymphoid tissues. They express the CLEC2 ligand podoplanin, and they create a three-dimensional network facilitating antigen transport and leukocyte migration.
- Myeloid-derived suppressor cells
(MDSCs). A heterogeneous population of cells of myeloid origin that have the ability to suppress T cell responses in multiple diseases. MDSCs can be further divided into monocytic MDSCs and neutrophilic MDSCs.
- Pattern recognition receptors
(PRRs). Receptors that bind to conserved molecular patterns normally found in pathogens (pathogen-associated molecular patterns (PAMPs)) but also to structures associated with cellular damage (damage-associated molecular patterns (DAMPs)). Examples of PAMPs include β-glucans and lipopolysaccharide. Examples of DAMPs include F-actin and spliceosome-associated protein 130 (SAP130).
- Neutrophil extracellular traps
(NETs). Extracellular structures consisting of DNA, hydrolytic enzymes and other antimicrobial components that are produced following the induction of a defined cell death programme in neutrophils. NETs, and similar structures produced by other cell types, trap and kill microorganisms extracellularly.
In the immunological context, adjuvants are compounds that potentiate or boost the immunogenicity of an antigen. Adjuvants are required to improve the effectiveness of vaccines, as they stimulate innate immune responses that promote the development of adaptive immunity to the vaccine antigens.
An intracellular uptake mechanism that induces the membrane enclosure of intracellular components and their targeting to the lysosomal pathway for degradation.
- Cytotoxic T lymphocyte
(CTL). CTLs are CD8+ T cells that can kill infected, transformed or damaged cells. CTLs recognize cellular antigens that are presented in the context of MHC class I molecules, which can trigger their cytotoxic activities either directly, through the release of perforin, granzymes and granulysin that enter and kill the target cells, or indirectly, through expression of FAS ligand, which binds to FAS on the surface of target cells, inducing a death-associated intracellular signalling pathway.
- Genome-wide association studies
(GWAS). Genetic sequencing studies used to determine whether a genetic variant (normally a single-nucleotide polymorphism) found within a population is associated with a trait of interest, such as a specific disease.
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Brown, G.D., Willment, J.A. & Whitehead, L. C-type lectins in immunity and homeostasis. Nat Rev Immunol 18, 374–389 (2018). https://doi.org/10.1038/s41577-018-0004-8
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