C‐type lectin‐like receptors on myeloid cells

Abstract

Host defence against pathogens requires the recognition of conserved microbial molecules, or ‘pathogen‐associated molecular patterns’ (PAMPs), by their receptors termed ‘pattern recognition receptors’ (PRRs), represented most notably by toll‐like receptors (TLRs) and C‐type lectins. The ‘non‐classical’ C‐type lectins (these that lack the residues involved in calcium binding, required for carbohydrate binding) are traditionally thought of as being restricted to natural killer (NK) or T cells, playing important roles in immune surveillance. In recent years, however, a growing number of these receptors have been identified on myeloid cells, both of human and mouse origin. In contrast to their NK counterparts that primarily control cellular activation through recognition of major histocompatibility antigen (MHC) class I and related molecules, the myeloid‐expressed receptors appear to have a far more diverse range of functions and ligands, including those of exogenous origin. Some of C‐type lectin‐like molecules possess activating/inhibitory signalling motifs that trigger downstream signalling events, suggesting the role for these receptors as positive/negative regulators of granulocyte and monocyte functions.

With the exception of a few myeloid NK‐like lectins, the natural ligands for most of these receptors remain unidentified, making it difficult to define their functions in normal physiological, inflammatory or pathological conditions. Importantly, in some cases, these novel C‐type lectin‐like lectins, encoded by genes from the same gene cluster, can act as receptor/ligand pairs, additionally contributing to the regulation of myeloid cell functions or their interaction with other (like NK) cell types. However, the relevance and importance of such interactions still needs to be assessed. Although few of the myeloid‐expressed C‐type lectins have been characterized in detail, we review here each of these receptors and highlight their prospective roles in innate and adaptive immunity.

• C‐type lectins
• innate immunity
• macrophages
• myeloid cells
• receptors

Introduction

In order to execute their functions, leukocytes interact with a broad range of various cell types both directly and through soluble factors. This recognition is mediated by a repertoire of flexible, yet specific and regulated surface molecules that are involved in the ‘sensing’ of a ligand, but may additionally guide leukocyte development, migration, differentiation, proliferation, maturation and survival. Cell surface receptors also afford the distinction of host versus foreign molecules and mediate the complex intercellular communications that coordinate various components of an immune response. Of particular interest are the family of natural killer (NK) and T‐cell expressed C‐type lectin‐like receptors, whose study has provided new insights into the mechanisms of immune recognition of transformed or infected host cells. A growing number of these receptors have now been identified on myeloid cells and, although few have been characterized in great detail, they appear to have far more divergent functions and ligands than their NK‐counterparts.

The characteristic feature of C‐type lectins is the presence of a C‐type lectin‐like domain (CTLD) fold, which is usually derived from six conserved cysteine residues 1. Receptors that contain CTLDs include the ‘classical’ and ‘non‐classical’ molecules, and have been classified into 14 groups or lectin subfamilies 2, based on the configuration of their CTLDs. The classical C‐type lectins are the largest and most diverse lectin family and comprise receptors that can bind glycan ligands in a calcium‐dependent manner 3. The non‐classical C‐type lectin receptors share structural homology with their classical counterparts, but lack the residues involved in calcium binding in the CTLD 4. The members of this family have evolved to recognize non‐sugar ligands, such as the major histocompatibility antigen (MHC) class I or related molecules, but some may be able to recognize carbohydrates via alternative mechanisms 5–7. We will focus on the group V C‐type lectins, that consists of the type II transmembrane, single CTLD‐containing, non‐classical molecules, which includes all the myeloid‐expressed NK‐like C‐type lectin‐like receptors (NKCL), and will review important aspects regarding their sequence, structure, expression pattern and function.

Key messages

• Myeloid‐expressed natural killer (NK)‐like C‐type lectins have diverse ligands and cellular functions, compared to their NK counterparts.

• These receptors play important roles in both innate and adaptive immunity through their ability to modulate myeloid cell functions.

General features

The group V NKCLs are usually encoded by six exons and share a common structure, comprising an extracellular CTLD, a stalk region of variable length, a transmembrane region and a cytoplasmic tail which may contain signalling motifs (Figure 1) 8. Most of their genes are located within a single genetic locus, the natural killer complex (NKC), located on chromosome 12 in humans and chromosome 6 in the mouse 9,10. Some of the NKCLs are clustered into distinct groups with this complex, including the myeloid and/or endothelial cell‐expressed cluster consisting of Dectin‐1, lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), C‐type lectin‐like receptor (CLEC‐1), CLEC‐2 and Myeloid inhibitory C‐type lectin‐like receptor (MICL) 11. Many contain cysteine residues within the stalk region, which appear to be involved in homo‐ or hetero‐dimerization. Many C‐type lectin/lectin‐like receptor (CTLR) genes are alternatively spliced and some are even trans‐spliced 12, though the functional significance of this is unclear. The variably spliced isoforms can encode lectins which lack the stalk or transmembrane regions, resulting in retention of the receptor within the cytoplasm or the generation of soluble forms of the receptor, respectively 13,14. Alternative splicing may also give rise to isoforms with different cytoplasmic tails, influencing receptor functions.

Figure 1. Structure of NK‐like C‐type lectins. NKCLs are encoded by six exons, and are type II transmembrane proteins consisting of a single extracellular C‐type lectin‐like domain, a stalk region, a transmembrane region and a cytoplasmic tail. These receptors can be glycosylated (represented by the lollipop structures), and may possess inhibitory ITIM (such as MICL) or activation ITAM‐like (such as Dectin‐1) motifs in their cytoplasmic tails. Many NKCLs (such as MDL‐1) lack cytoplasmic signalling motifs but associate through charged residues in their transmembrane domains with the activation or costimulatory signalling molecules, DAP10 or DAP12. Abbreviations to Figure 1: cyto ‐ cytoplasmic part of receptor TM ‐ Transmembrane CTLD ‐ C‐type lectin‐like domain ITIM ‐ immunoreceptor tyrosine‐based inhibitory motif ITAM ‐ immunoreceptor tyrosine‐based activation motif hMICL, mBGR, MDL ‐ names of receptors in Figure 1 as well as in Table 1 are explained in detail in the text.

The NKCLs can be functionally divided into activating or inhibitory receptors, depending on their cytoplasmic signalling motifs or association with distinct signalling molecules. In general, inhibitory receptors possess cytoplasmic immunoreceptor tyrosine‐based inhibition motifs (ITIM), whereas activating receptors associate via charged residues in their transmembrane domains with adaptor molecules, such as DAP12, which possess the immunoreceptor tyrosine‐based activation motifs (ITAM). The mechanisms and kinase and phosphatase activation involved in these ITAM‐ and ITIM‐mediated signalling events are well characterized in T, B and NK‐cells and are described elsewhere 15. Some myeloid‐expressed activation receptors, however, such as Dectin‐1, contain ITAM‐like motifs in their cytoplasmic tail which can directly trigger cellular responses through novel and mostly undefined signalling pathways.

For many myeloid‐expressed NKCLs, the natural ligands are unknown and their biological functions have rarely been investigated in detail (summarized in Table I). In addition to MHC class I and related molecules, these NKCLs have been shown to recognize a broad range of structurally unrelated, exogenous and endogenous ligands including bacterial 16, fungal 6 and viral proteins 17, tumour‐derived antigens 18 and modified low‐density lipoprotein (LDL) 19. The recognition of microbial components suggests that some members function as non‐opsonic pattern recognition receptors. On antigen presenting cells, some of these receptors may contribute to the activation and maturation of lymphocytes 20, whereas others are involved in the interaction with NK cells, modulating their activation and functions 21. Although the mechanisms of these interactions are unclear in most cases, the function of NKCLs suggests that they may contribute to both innate and adaptive immune responses.

Table I. Myeloid‐expressed NK C‐type lectin‐like receptors.

Receptor		Distribution	Ligands	Regulation	Proposed and predicted functions
In human	In mouse
LOX‐1	LOX‐1	Endothelial cells, platelets, macrophages, smooth muscle cells	Oxidized LDL, red blood cells, human Hsp70, S. aureus, E. coli, aged or apoptotic cells	Oxidized LDL pro‐inflammatory stimuli (TNF‐α, LPS), fluid shear and oxidative stress	Scavenger receptor, PRR ^a for bacteria
BGR	Dectin‐1	Macrophages, monocytes, neutrophils, dendritic cells, subsets of T cells	β‐1,3 and β‐1,6‐ glucans, zymosan, C. albicans, S. cerevisae, P. carinii, A. fumigatis, C. posadasii ligand on T cells	Up‐regulated by PMA ^b, IL‐4 ^c, IL‐13, GM‐CSF ^d down‐regulated by IL‐10, LPS, TNF‐α,IL‐1β	PRR for fungi, activation of CD4^+ and CD8^+ T cells
CLEC‐1 CLEC‐2	Clec‐1 Clec‐2	DC, liver, endothelial and myeloid cells, platelets	Unknown, rhodocytin	Unknown, unknown	Unknown, platelet activation
unknown	Ly49q	Foetal liver mononuclear, DC, NKT ^e and NK cells, activated macrophages	Unknown	Maturation status of cells, IFN‐α or IFN‐γ stimulation	Possible role during viral infection, regulation of macrophage cytoskeletal architecture
MICL	Micl	Malignant and normal myeloid cells, DC, NK, T cells, macrophages	Unknown	Unknown	Inhibition of NK cell cytotoxicity, together with CD33 marker for AML ^f
KLRF‐1	unknown	PBLs ^g, NK cells, subsets of T cells, myeloid cell lines	Unknown receptor on T cells	Unknown	Regulation of NK and possibly monocyte activity, regulation of T cell functions
MDL‐1	? Mdl‐1	Monocytes, subsets of DC, macrophages, monocytes‐ and macrophage cell lines	Unknown	Maturation status of cells, mycobacterial infection, LPS, TNF‐α, IFN‐γ	Role in antimicrobial immunity, activation of macrophage functions
CD69	Cd69	Activated lymphocytes, neutrophils, monocytes, macrophages, NK and B cells, platelets, Langerhans cells	Unknown	Cytokines, microbial stimuli	Activation of NK, T and mast cells, MØ and monocytes, involved in bacteria clearance, cell adhesion, type I hypersensitivity and angiogenesis
LLT1	Clr‐b, Clr‐f, Clr‐g	Macrophages, DC, NK, T and B cells	NKR‐P1A, Nkrp1d, Nkrp1f glycosaminoglycans (dextran sulphate, fucoidan)	Maturation state of cells, prostaglandin E2, IL‐1α, calciotropic agents, PMA, IL‐2	Role in osteoclast differentiation, modulation of NK cell function, T cell activation

^a Pattern recognition receptor

^b Phorbol 12‐myristate 13‐acetate

^c Interleukin

^d Granulocyte‐macrophage colony‐stimulating factor

^e Natural killer T cell

^f Acute myeloid leukaemia

^g Peripheral blood leukocytes

LDL low‐density lipoprotein; Hsp70 heat shock protein; TNF‐α tumor necrosis factor alpha; LPS lipopolysaccharide; NK natural killer; IFN‐γ interferon gamma; MØ macrophages. The names for receptors are explained in detail in the text.

LOX‐1(CLEC8A): a scavenger receptor

Lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) was originally isolated from a bovine aortic endothelial cDNA expression library, screened for receptors for oxidized LDL (OxLDL). In addition to vascular endothelial cells, the receptor is expressed on macrophages, fibroblasts, platelets and smooth muscle cells 22–26. The receptor can also be cleaved and released from the cell surface, producing a soluble form with unknown function. The level of surface LOX‐1 expression is regulated by fluid shear, oxidative stress, pro‐inflammatory stimuli (such as tumour necrosis factor alpha (TNF‐α)) and by OxLDL itself 27–31. Furthermore, LOX‐1 expression may be enhanced in certain pathological states, including atherosclerosis, hyperlipidaemia, diabetes and hypertension 19,32,33.

LOX‐1 is functionally classified as a scavenger receptor due to its ability to recognize modified forms of low‐density lipoprotein. In addition, LOX‐1 is able to recognize aged/apoptotic cells, human heat shock protein (Hsp70), red blood cells and activated platelets, as well as Gram‐positive and Gram‐negative bacteria, serving in the last case as a pattern recognition receptor 22,34–36. Although the cytoplasmic tail of LOX‐1 lacks any conserved signalling motif, this receptor can initiate several cellular events such as ligand internalization, nuclear factor‐κB (NFκB) activation, apoptosis as well as the respiratory burst and cytokine production 22,30,34,37,38. Through the interactions with Hsp70, LOX‐1 has been implicated in dendritic cell‐mediated antigen cross‐presentation 39. Others have suggested a function for LOX‐1 as a cell adhesion molecule involved in leukocyte recruitment during inflammation 40. However, LOX‐1 can induce pathological changes in endothelial cells after exposure to OxLDL and has been primarily studied as having a potential role in atherogenesis 31,32.

Dectin‐1(CLECSF12): A β‐glucan receptor

Dectin‐1 (Beta‐glucan receptor; BGR) was first identified as a receptor on dendritic cells which recognized an unidentified ligand on T cells, but was later re‐identified as a receptor for β‐glucan polysaccharides 6,41–43. In human and mouse Dectin‐1 is expressed in a tissue specific manner on macrophages, monocytes, dendritic cells, neutrophils, and some subsets of T cells and the human receptor is also expressed on B cells 44–47. Surface expression of Dectin‐1 can be regulated by cytokines and other agents, including microbial components 47. Dectin‐1 can be alternatively spliced and contains a non‐classical ITAM‐like motif in its cytoplasmic tail which is capable of triggering various cellular responses, including phagocytosis, synthesis of reactive oxygen intermediates (ROIs) and cytokine production 48–51. Signalling from the ITAM‐like motif is complex and cell specific and involves a number of pathways, including a novel interaction with spleen tyrosine kinase (Syk) kinase and collaborative signalling with the toll‐like receptors 48,49,52.

1 acts as a pattern recognition receptor for β‐1,3 and/or β‐1,6 glucans and is the major leukocyte receptor for these carbohydrates 6,45. From primarily in vitro analysis, Dectin‐1 is thought to play an important role in the innate immune response to fungal pathogens, and has been shown to recognize a number of these organisms, including Candida albicans45, Aspergillus fumigatus, Pneumocystis carinii53 and Coccidioides posadasii54. Through recognition of these carbohydrates, Dectin‐1 can also induce autoimmunity and disease in specific genetic backgrounds 55. In SKG mice (which are prone to develop autoimmune arthritis) zymosan and other β‐glucan particles stimulate dendritic cells (DCs) to secrete cytokines and to present self‐antigens to arthritogenic T cells, leading to chronic arthritis. The activation of DCs takes place in a Dectin‐1‐dependent manner, and the blockage of this receptor prevents the onset of disease 55. Lastly, Dectin‐1 has also been shown to play a role in thymocyte development and/or T cell activation, although the nature of this interaction and the endogenous T cell ligand is unknown 20,41,44.

CLEC‐1 and ‐2

In comparison with Dectin‐1 and LOX‐1, much less is known about CLEC‐1 and ‐2, two NKCLs identified from searches of expressed sequence tags (EST) databases. Human CLEC‐1 was shown to be selectively expressed in two or more transcripts by activated dendritic cells (DC) and endothelium 11. However, as CLEC‐1 does not reach the cell surface in endothelial or fibroblast‐like cell line transfectants, it is likely that this receptor requires a partner molecule for surface expression 56. CLEC‐2, in contrast, appears to be expressed as one transcript mainly on myeloid cells 56 and platelets 57. Both CLECs contain potential cytoplasmic signalling sequences with that of CLEC‐2 resembling the endocytic motifs of asialoglycoprotein receptor 1 (ASGPR‐1, also known as hepatic lectin H1 or C‐type lectin domain family 4, member H1 (CLEC4H1)) and DC‐specific ICAM‐grabbing nonintegrin (DC‐SIGN) 56. The YXXL motif of CLEC‐2 was recently shown to become phosphorylated during platelet activation, induced by the snake venom component rhodocytin, leading to the binding of Syk kinase and downstream phosphorylation events, including the activation of phospholipase C gamma (PLCγ2) 57. Given its homology to the natural‐killer group 2 (NKG2) and Ly49 molecules, CLEC‐2 has been tested for binding to certain classical and non‐classical MHC class I tetramers, but no interaction has been detected 56. The endogenous and/or exogenous ligands and physiological functions of CLEC‐1 and CLEC‐2 receptors remain to be described.

Ly49q

The members of the Ly49 family are perhaps the best known NK‐like C‐type lectins, and although expressed almost exclusively on NK and T cells, Ly49q is the one exception, being expressed on myeloid precursors in the bone marrow, foetal liver, spleen and peripheral blood, and on activated macrophages 58,59. The level of Ly49q surface expression depends on the maturation status of cells, with immature precursors expressing high levels of Ly49q, while mature cells are Ly49q low to negative 59. Ly49q also has a defined expression pattern on different dendritic cell subsets 58, being highly expressed on plasmacytoid DC but absent on myeloid DC 58,60. Three different allelic forms of Ly49q have been identified and expression of the receptor can be up‐regulated by both type I and type II interferon (IFN) 58,59. The ligand of Ly49q has not been identified, but it is likely to be an MHC class I or related molecule, based on the similarity of this receptor to the other Ly49 family members. Ly49q contains a cytoplasmic ITIM motif that can bind SH₂‐domain‐containing protein tyrosine phosphatase 1 (SHP‐1) and SHP‐2 phosphatases, and has been shown through antibody cross‐linking to be able to regulate cytoskeletal architecture in macrophages, but not in plasmacytoid DC 59,61. The physiological role of this receptor is unknown.

MICL(CLEC12A)

The gene encoding human myeloid inhibitory C‐type lectin‐like receptor (MICL, also known as killer cell lectin‐like receptor 1 (KLRL1), C‐type lectin‐like molecule‐1 (CLL‐1) or dendritic cell‐associated C‐type lectin 2 (DCAL‐2)) is positioned at the telomeric end of the gene cluster encoding LOX‐1, Dectin‐1, CLEC‐1 and CLEC‐2 within the NK gene complex 11. In addition to the basic NKCL structure, MICL is highly glycosylated, has two extra cysteines in the stalk region, which may allow homo‐ or hetero‐dimerization, and contains an archetypal ITIM in its cytoplasmic tail 62. MICL is alternatively spliced and its expression is restricted to myeloid cells, including granulocytes, monocytes, macrophages and dendritic cells, although MICL transcript has also been detected in NK and T cells 62–64. Although the ligand for MICL is unknown, the receptor can associate with SHP‐1 and SHP‐2 phosphatases and analyses with chimeric constructs indicated that MICL can inhibit cellular activation 62. Recently, antibody cross‐linking experiments have shown that MICL can alter dendritic cell responses to toll‐like receptor (TLR) agonists and their interaction with T cells 65.

KLRF1

Killer cell lectin‐like receptor, subfamily F, member 1 (KLRF‐1, also called NKp80) is alternatively spliced, producing a number of isoforms with differing subcellular localizations 10,66. KLRF‐1 contains two non‐typical tyrosine based motifs in the cytoplasmic tail and is expressed as a dimer in activated NK cells, subsets of T cells, peripheral blood leukocytes, and some myeloid cell lines 10. This receptor may recognize an unidentified ligand on T cells, and the stimulation of NK cells with anti‐KLRF‐1 antibodies induces cytolytic activity and Ca²⁺ mobilization 67.

MDL‐1

Myeloid DAP12‐associating lectin 1 (MDL‐1) was isolated through a screen for receptors which associated with the activating signalling molecule DNAX‐activating protein of 12 kDa (DAP12, known also as killer activating receptor associated protein (KARAP)), and is distinct from other NKCLs in that it is located on chromosome 7. MDL‐1 is alternatively spliced, lacks a cytoplasmic tail and possesses a charged residue in its transmembrane region, which mediates the interaction with DAP12 68. The receptor is expressed in monocytes and macrophages and has been identified in some DC subsets, although it appears to be down‐regulated upon monocyte differentiation into DCs 68–70. Chimeric analyses have suggested that stimulation of MDL‐1 can induce Ca²⁺ mobilization, although the ligand for this receptor is unknown, and recent studies have shown that MDL‐1 expression is induced during mycobacterial infection in vivo, suggesting a role in antimicrobial immunity 68,71.

CD69

CD69, or activation inducer molecule (AIM), is expressed as a variably glycosylated, disulfide‐linked homodimer 72–74. Dimerization and surface expression is dependent on cysteine residues in the stalk of this receptor 7. Although CD69 was first identified as a lymphocyte activation marker 75, the receptor is widely expressed on other cell types, including NK and B cells, neutrophils, monocytes, macrophages, platelets and Langerhans cells 76, and the levels of expression can be regulated by cytokines and other agents, including microbial stimuli 77.

The cytoplasmic domain of this receptor can be phosphorylated on serine residues and is able to transduce Ca²⁺ dependent signalling that results in various effector functions, depending on the cell type 7,78–81. CD69 can activate cytokine secretion by T cells 82, the release of lysozyme by neutrophils 83 and potentiate FcϵRI receptor signalling in mast cells 78. Cross‐linking of CD69 in monocytes and macrophages induces extracellular Ca²⁺ influx, nitric oxide production, cytotoxicity, cytokine production and some antimicrobial responses 84–86. CD69 cross‐linking also affects NK cell cytotoxicity, proliferation, the expression of adhesion molecules and cytokine production 87,88. Interestingly, these effects could be negatively regulated by the inhibitory CD94/NKG2A complex 81. Recently, CD69 was shown to be involved in cell aggregation and adhesion, and in angiogenesis, through an association with calreticulin 89. CD69 deficient mice have been generated, and although the development of hematopoietic cells in CD69^−/− mice is mostly normal, some alterations in B cell maturation were observed 90. Studies of these mice have demonstrated that CD69 may function as a negative regulator of anti‐tumour responses and of autoimmune reactivity and inflammation 91,92.

Clr

A new family of seven C‐type lectin‐related (Clr a‐g) molecules that lack some of the conserved cysteines involved in disulfide bridge formation of the CTLD have recently been identified in mice 93,94. These receptors also lack apparent cytoplasmic signalling motifs or charged transmembrane residues 95. The various members of the Clr family have distinct tissue distributions and are expressed on numerous cells, including activated NK cells, T and B cells, monocytes and macrophages. Their expression can be regulated by the maturation state of the cells as well as by cytokines and other agents 94–97.

Despite its unusual carbohydrate recognition domain (CRD), the most characterized Clr, Clr‐b (also known as osteoclast‐derived inhibitory lectin (OCIL)), is able to recognize and bind certain glycosaminoglycans in a Ca²⁺‐independent manner 98. Clr‐b, as well as Clr‐d (OCILrP1) and Clr‐g (OCILrP2, LCL‐1, CLEC2I, Dcl1) have been shown to play an important role during osteoclast differentiation in vitro, although the mechanisms of this regulation are unclear 93–95,98,99. The Clr proteins have been identified as ligands for the NK‐specific natural killer cell receptor protein 1 (Nkrp1) family of NKCLs. The interaction between Clr and Nkrp1 appears to be specific for each family member, and results in modulation of NK cell function 95,96. Clr‐g, which is exclusively expressed in spleen and thymus, was recently shown to be involved in lymphocyte activation through an interaction with its cognate ligand on antigen‐presenting cells 100. In contrast to mouse, which has multiple Clr family genes, human possesses only one ortholog receptor called CLEC2D or lectin‐like transcript 1 (LLT1) 97. LLT1 is predominantly expressed by monocytes and B cells, as well as by phorbol 12‐myristate 13 acetate (PMA)‐stimulated peripheral blood mononuclear cells (PBMCs) and IL‐2 activated NK and T cells 101,102. Like mouse Clr‐b, human LLT1 blocks osteoclast differentiation 94,97 and can induce IFN‐γ production by NK cells upon cross‐linking with an antibody 101. Very recently two independent groups have shown that LLT1 is a ligand for human NKR‐P1A, and that the LLT1‐NKR‐P1A interaction leads to the inhibition of NK cell cytotoxicity and IFN‐γ secretion 103,104. By contrast, in T cells the NKRP‐1A‐LLT1 interaction enhances T cell receptor (TCR)‐dependent IFN‐γ secretion 103, suggesting that the new ligand/receptor pair differentially regulate NK and T cell functions.

Conclusion

The numbers of known activation and inhibitory NKCLs have increased considerably in the past decade and many novel members are still being identified and characterized. While the role of these receptors on NK cells appears to be primarily the detection of aberrant, transformed or virally infected cells, the NKCLs appear to serve far more divergent functions on myeloid cells. However, beyond their initial characterization, little is known about their physiological functions in vivo. In addition, the inhibitory and activation mechanisms triggered by these receptors appear to be novel, but are mostly undefined.

The identification of the ligand(s) of these receptors remains one of the major challenges in the field. It is possible that the ligands are expressed at low levels or at specific sites or during a particular window in ontogeny, or are expressed only upon stress, infection or ageing. The ligands may also be exogenous, and some NKCLs act as pattern recognition receptors. Undoubtedly, the future study of these receptors will give more insights into myeloid cell biology, and may provide alternative targets for the modulation of myeloid cell function for the treatment of infectious and non‐infectious diseases.

Acknowledgements

We are grateful to Dr. Janet Willment and Dr. Kevin Dennehy for reviewing the manuscript. We thank the South African National Research Foundation, the Wellcome Trust and Medical Research Council. Gordon D. Brown is a Wellcome Trust International Senior Research Fellow in Biomedical Science in South Africa.