REVIEWS Signalling through C-type lectin receptors: shaping immune responses Teunis B. H. Geijtenbeek and Sonja I. Gringhuis Abstract | C‑type lectin receptors (CLRs) expressed by dendritic cells are crucial for tailoring immune responses to pathogens. Following pathogen binding, CLRs trigger distinct signalling pathways that induce the expression of specific cytokines which determine T cell polarization fates. Some CLRs can induce signalling pathways that directly activate nuclear factor‑κB, whereas other CLRs affect signalling by Toll‑like receptors. Dissecting these signalling pathways and their effects on host immune cells is essential to understand the molecular mechanisms involved in the induction of adaptive immune responses. In this Review we describe the role of CLR signalling in regulating adaptive immunity and immunopathogenesis and discuss how this knowledge can be harnessed for the development of innovative vaccination approaches. Dendritic cells (DCs) are located throughout the body Triggering of several PRRs simultaneously can induce T helper (TH) cell A T cell subset that secretes a to capture and internalize invading pathogens, and diverse innate immune responses, which provides the distinct set of cytokines after subsequently process and present antigen on MHC diversity that is required to shape an effective adaptive activation, which occurs class I and class II molecules to CD8+ and CD4+ T cells, immune response. Distinct pathogens express different through the ligation of the T cell respectively1. Antigen presentation by DCs is in itself PAMPs, and the combination of these PAMPs functions receptor with its cognate ligand (peptide–MHC complex), not sufficient to induce effective T cell responses against as a fingerprint that triggers a specific set of PRRs, lead‑ + together with the recognition of pathogens. CD4 T cells need to differentiate into dis‑ ing to the integration of signalling pathways to tailor the the appropriate co-stimulatory tinct T helper (TH) cell subsets depending on the type of immune response to that specific pathogen. molecules. Naive T cells H infection; T 1 cells secrete interferon‑γ (IFNγ), which Recent studies have identified CLRs as an impor‑ differentiate into T 1, T 2 or H H H activates macrophages to fight intracellular micro‑ tant family of PRRs that are involved in the induction TH17 cells, depending on the cytokines and co-stimulatory organisms, TH2 cells secrete interleukin‑4 (IL‑4), IL‑5 of specific gene expression profiles to specific patho‑ molecules presented to them and IL‑13 to induce humoral immune responses against gens, either by modulating TLR signalling or by directly by antigen-presenting cells. 3–6 helminths, and IL‑17‑secreting TH17 cells mobilize inducing gene expression . In this Review we discuss the phagocytes to clear extracellular fungi and bacteria1. recently published literature describing the innate signal‑ Regulatory T cell regulatory T cells A T cell belonging to a Furthermore, are needed to control the ling pathways induced by CLRs and describe how these + specialized subset of CD4 activity of effector TH cells. Thus, DCs need to translate pathways can be used in vaccine development to tailor T cells that suppresses information about the invading pathogen into a cytokine specific immune responses for the treatment of not only immune responses to maintain gene expression profile that directs the correct T cell infectious diseases but also cancer and immunological tolerance to antigens, including H self antigens. differentiation pathway. diseases such as allergy and autoimmunity. Pathogen recognition is central to the induction of Center for Experimental and T cell differentiation. Although the variety of pathogens CLRs as signalling receptors Molecular Medicine and is immense, groups of pathogens share similar struc‑ The term C‑type lectin was introduced to distinguish Center for Infection and tures known as pathogen-associated molecular patterns between Ca2+‑dependent and Ca2+‑independent car‑ Immunity Amsterdam, 2 Academic Medical Center, (PAMPs), which enable their recognition . DCs express bohydrate‑binding lectins. CLRs share at least one University of Amsterdam, numerous pattern recognition receptors (PRRs) that carbohydrate recognition domain, which is a compact Meibergdreet 9, 1105 AZ interact with PAMPs to induce cytokine expression. structural module that contains conserved residue Amsterdam, The Netherlands. PRRs include the archetypical Toll‑like receptors (TLRs), motifs and determines the carbohydrate specificity of Correspondence to T.B.H.G. as well as non‑TLRs such as intracellular nucleotide‑ the CLR7. The CLR family now includes proteins that e-mail: [email protected] binding domain and leucine‑rich‑repeat‑containing have one or more domains that are homologous to carbo‑ doi:10.1038/nri2569 family (NLRs), retinoic acid‑inducible gene I (RIG‑I)‑ hydrate recognition domains but do not always bind Published online 12 June 2009 like receptors and C‑type lectin receptors (CLRs)2. carbohydrate structures7. CLRs exist both as soluble and NATURE REVIEWS | IMMUNOLOGY VOLUME 9 | JULY 2009 | 465 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS transmembrane proteins. In this Review we discuss the activator protein 1 and members of the IFN regulatory transmembrane CLRs that function as PRRs. These CLRs factor family by diverse PRRs provides flexibility and can be divided into two groups: group I CLRs belong to variability to the regulation of cytokine gene expres‑ the mannose receptor family and group II CLRs belong sion, which is needed to combat different pathogens2,19. to the asialoglycoprotein receptor family and include the CLR‑induced signal transduction seems to mainly acti‑ DC‑associated C‑type lectin 1 (dectin 1; also known as vate or modulate NF‑κB functions, and the regulation CLEC7A) and DC immunoreceptor (DCIR; also known of other transcription factors by CLRs has received as CLEC4A) subfamilies (TABLE 1). little attention to date. In the following sections we CLRs expressed by DCs interact with pathogens pri‑ first discuss the signalling pathways induced by CLRs marily through the recognition of mannose, fucose and that modulate TLR‑induced gene expression and then glucan carbohydrate structures. Together, these CLRs describe the mechanisms used by CLRs to induce gene recognize most classes of human pathogens; mannose expression by themselves. specificity allows the recognition of viruses, fungi and mycobacteria, fucose structures are more specifically CLR and TLR signalling crosstalk expressed by certain bacteria and helminths and glu‑ DC-SIGN signalling. DC‑SIGN interacts with a wide can structures are present on mycobacteria and fungi8,9. range of pathogens through mannose and fucose rec‑ Recognition by CLRs leads to the internalization of ognition (TABLE 1), and recent studies have shed more the pathogen, its degradation and subsequent antigen light on its signalling properties (FIG. 1). The interaction presentation9 (BOX 1). These properties are important of DC‑SIGN with mannose‑containing pathogens, such for vaccine design1. However, an even more powerful as Mycobacterium tuberculosis, Mycobacterium leprae, application has remained largely unexplored: targeting HIV‑1, measles virus and Candida albicans, affects of the signalling pathways downstream of CLRs to tailor TLR4‑mediated immune responses by DCs3,20. The immune responses to break tumour‑induced immuno‑ crosstalk between TLR4 and DC‑SIGN depends on suppression, to induce TH1‑type responses against virus the prior activation of NF‑κB by TLR signalling and is infections or to redirect allergic TH2 cell responses to therefore not limited to TLR4, but also includes trigger‑ protective TH1 cell responses. ing of other NF‑κB‑inducing PRRs, such as TLR3 and CLR triggering by different pathogens can induce TLR5 (REF. 3). DC‑SIGN triggering activates the serine/ diverse immune responses (TABLE 1). The underlying threonine protein kinase RAF1, which induces the phos‑ signalling processes are complex and depend on cross‑ phorylation of the NF‑κB subunit p65 at Ser276 (REF. 3). talk with other PRRs, the ligand‑ or carbohydrate‑ The activation of RAF1 by DC‑SIGN does not depend specific signalling pathway and the DC subset. Recent on TLR signalling3 and involves a complex sequence studies suggest that there are two general ways by of events, including its release from autoinhibition, which CLRs induce signalling pathways. CLRs, such dephosphorylation, transformational changes and as macrophage‑inducible C‑type lectin (mincle; also finally phosphorylation to activate its kinase activity21. known as CLEC4E), dectin 2 (also known as CLEC6A), Specifically, DC‑SIGN triggering activates the small blood DC antigen 2 protein (BDCA2; also known as GTPase Ras proteins, which is the first essential step CLEC4C) and C‑type lectin domain family 5, member A in RAF1 activation. Subsequent binding of GTP–Ras (CLEC5A), are associated with and induce signalling to RAF1 leads to the phosphorylation of RAF1 at residues pathways through immunoreceptor tyrosine‑based Ser338, Tyr340 and Tyr341 (REF. 3). Phosphorylation of activation motif (ITAM)‑containing adaptor mol‑ RAF1 at Ser338 is mediated by p21‑activated kinases ecules, such as Fc receptor γ‑chain (FcRγ) or DAP12 (PAKs), which in turn are activated by members of the (REFS 10–13). Other CLRs, such as dectin 1, DC‑specific Rho family of small GTPases, and phosphorylation ICAM3‑grabbing non‑integrin (DC‑SIGN; also