Macrophage Receptors and Immune Recognition: Annual Review of Immunology February 2005

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Macrophage receptors and immune recognition
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AR REVIEWS IN ADVANCE10.1146/annurev.immunol.23.021704.115816
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Annu. Rev. Immunol. 2005. 23:901–44
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doi: 10.1146/annurev.immunol.23.021704.115816
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D V A First published online as a Review in Advance on January 7, 2005
MACROPHAGE RECEPTORS AND IMMUNE

RECOGNITION
P.R. Taylor, L. Martinez-Pomares, M. Stacey, H-H. Lin,
G.D. Brown, and S. Gordon
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE,
United Kingdom; email: siamon.gordon@path.ox.ac.uk
Key Words pattern recognition, innate immunity, phagocytosis, micro-organisms,

apoptosis
■ Abstract Macrophages express a broad range of plasma membrane receptors that
mediate their interactions with natural and altered-self components of the host as well
as a range of microorganisms. Recognition is followed by surface changes, uptake,
signaling, and altered gene expression, contributing to homeostasis, host defense, in-
nate effector mechanisms, and the induction of acquired immunity. This review covers
recent studies of selected families of structurally defined molecules, studies that have
improved understanding of ligand discrimination in the absence of opsonins and dif-
ferential responses by macrophages and related myeloid cells.
INTRODUCTION
The surface receptors of the macrophage (MØ) and closely related myeloid cells
regulate a range of functions, including differentiation, growth and survival, adhe-
sion, migration, phagocytosis, activation, and cytotoxicity.1 With the development
of powerful immunologic and genetic tools, knowledge of membrane glycopro-
teins has grown rapidly, although the full repertoire of MØ surface-expressed
molecules remains to be determined. Their ability to recognize a wide range of
endogenous and exogenous ligands, and to respond appropriately, is central to MØ
functions in homeostasis as well as host defense in innate and acquired immunity,
autoimmunity, inflammation, and immunopathology (1–3). The role of classic op-
sonins (antibody and complement) in enhanced phagocytosis led the way; recent
research into sensing of a range of microbial ligands by Toll-like receptors (TLR)
and families of cytosolic proteins (e.g., NODs, NALPs) has been well documented
(4–6). In this review we focus on less well-known receptor families implicated in
nonopsonic recognition, mediating either cell adhesion or phagocytosis. We omit
1
See Appendix for a full list of abbreviations used.
0732-0582/05/0423-0901$14.00 901
902 TAYLOR ET AL.
TABLE 1 Overview of MØ receptors implicated in immune recognitiona

Receptor family Example Function (example)
Scavenger (collagenous) SR-A Phagocytosis of bacteria and

apoptotic cells, endocytosis of
modified LDL, adhesion
Scavenger (noncollagenous) CD36 Phagocytosis of apoptotic cells,
diacyl lipid recognition of
bacteria
GPI-anchored CD14 LPS-binding protein/interactions
MD2/MyD88, TLR signaling,
apoptotic cell recognition
Integrin CR3 Complement receptor (C3bi)
mediated phagocytosis
(CD18/11b) Adhesion to endothelium
Ig Superfamily FcR (ITAM/ITIM) Antibody-dependent binding,
uptake, killing
TREM-1 (ITAM) Regulation of inflammation
Seven transmembrane CCR2 Receptor for MCP-1
C5aR Chemotaxis, degranulation
EMR2 (EGF-TM7) Myeloid cell adhesion
Chondroitin sulphate binding
NK-like C-type lectin-like Dectin-1 β-glucan receptor, fungal
(ITAM-like) particle ingestion
TNFα release/interaction TLR2
C-type lectin (single CTLD) DC-SIGN Mostly DC, pathogen
recognition, ICAM adhesion
Multiple CTLD MR Clearance, alternative activation,
antigen transport?
Toll-like receptors TLR2 Response to Peptidoglycan
(Leucine-rich repeats) TLR4 Response to LPS
a
MØ express multiple receptors belonging to major structurally defined families. Examples shown are referred to in text.
detailed discussion of receptors for cytokines, chemokines, selectins, and inte-

grins, which have been extensively reviewed previously. We emphasize the nature,
expression, and roles of structurally diverse molecular families, loosely but not
exclusively linked to particular immune recognition functions of MØ (Table 1).
We consider evolving concepts of pattern recognition in relation to phagocytic
uptake of microbes and apoptotic cells and summarize key findings and issues
for further research. Supplemental information and references are also available;
follow the Supplemental Material link from the Annual Reviews home page at
http://www.annualreviews.org.
MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 903
PATTERN RECOGNITION, AN EVOLVING CONCEPT

The concept of pattern recognition, proposed by Janeway and subsequently
Medzhitov (7), has been extraordinarily fruitful and has stimulated research into
the field of immune recognition by antigen-presenting cells (APC). It is based on
the recognition of conserved microbial structures, so-called pathogen-associated
molecular patterns (PAMPs), by a limited number of germ line–encoded APC pat-
tern recognition receptors (PRR). By contrast, somatic recombination generates a
large repertoire of T and B cell receptors for mainly peptide antigens. This proposal
was linked to the induction of costimulatory molecules on APC, essential to stim-
ulate lymphocyte responses. The subsequent discovery of TLR and their signaling
pathways in insects and vertebrates added considerable weight to the hypothesis.
The original concept needs to be refined with advancing molecular charac-
terization of receptor-ligand interactions. Natural ligands on microorganisms are
still poorly defined and include nonessential proteins (e.g., flagellin) as well as
lipopolysaccharide (LPS), peptidoglycans (PGN), and related molecules. Clearly,
these molecules are also expressed by commensal and opportunistic pathogenic or-
ganisms. To take this into account, researchers have suggested anatomical seques-
tration of organism and host. In addition, several PRR interact with endogenous,
host-derived as well as exogenous microbial ligands. This brings into question
the mechanisms of sensing and intracellular signaling that generate diverse pro- or
anti-inflammatory responses. What is not in doubt is that the APC repertoire is very
broad, encompassing protein, carbohydrate, lipid, and nucleic acid ligands; recep-
tor diversity is markedly increased by combinatorial expression, alternate splicing
to generate multiple isoforms, post-translational glycosylation, lipid modifications
and proteolysis. Comparative genomic studies in Drosophila, C. elegans, and other
invertebrates have identified large numbers of lectin-like and scavenger receptor
cysteine-rich (SRCR) domain-containing molecules, as well as leucine-rich do-
main molecules related to TLR. Although most of these putative receptors remain
orphans, their abundance attests to the ancient evolutionary origins of innate recog-
nition mechanisms.
TLRs in vertebrates are able to sense diverse, microbial, and other ligands
and to transmit signals via adaptor molecules selectively, but they depend on
other surface molecules such as CD14/MD2 (4) and C-type lectin-like receptors
(8) for proximal ligand binding and recognition. Collaboration among different
membrane receptor families, as well as with nonclassical opsonins and proteinase
cascades such as complement, is likely to be an important mechanism to enhance
affinity of binding and specificity. Some nonopsonic receptors display low-affinity,
promiscuous binding, in the case of SR-A, to many polyanionic structures (9);
however, others have high-affinity binding for specific ligands, e.g., Dectin-1.
Ligand structures may themselves display considerable promiscuity in binding to
multiple receptors.
Finally, cellular expression of each receptor is tightly regulated on monocyte-
MØ, myeloid dendritic cells (DCs), and polymorphonuclear leukocytes (PMN)
904 TAYLOR ET AL.
during their differentiation, migration into different tissue microenvironments,

and cell activation. This increases the complexity of receptor interactions with
neighboring cells, as well as with extracellular matrix and constituents of plasma
and lymph.
HETEROGENEOUS ANTIGEN AND SURFACE

RECEPTOR PHENOTYPE OF TISSUE MØ
Most resident MØ in the normal adult are derived from circulating bone marrow–
derived monocytes. Blood monocyte-like cells also give rise to related DCs and
osteoclasts (1). Studies of the expression of differentiation antigens and surface
receptors with monoclonal antibodies (mAb) have shown that tissue MØ become
markedly heterogeneous and express very different phenotypes, reflecting spe-
cialization of function within particular microenvironments. As well as distinct
subpopulations in lymphoid organs, MØ are found in nonlymphoid organs like the
liver (Kupffer cells), lung (alveolar MØ), nervous system (microglia), epidermis
(Langerhans cells), reproductive organs, and serosal cavities. MØ are also found
within the lamina propria of gut and the interstitium of organs such as the heart,
pancreas, and kidney. In response to inflammatory and immune stimulation, ad-
ditional monocytes are recruited in increased numbers to local sites, where they
display different phenotypes from originally resident MØ. It is convenient to distin-
guish “elicited” and “immunologically activated” MØ, depending on the cytokine
milieu. Newly recruited monocytes/MØ adapt to their local microenvironment and
become hard to distinguish from the original resident MØ, which themselves un-
dergo activation by local stimuli. Examples of surface heterogeneity of MØ and
DCs in some of these anatomical locations are summarized in Figure 1. Antigen
and receptor markers shown are described below.
MØ play a broad homeostatic role in clearance of senescent cells and in tissue
remodeling and repair after injury or infection. Analysis of the receptor mech-
anisms involved, for example in the clearance of apoptotic cells, has implicated
many receptors in the recognition process (see below). Many of the same receptors
mediate uptake of modified host lipoproteins, contributing to the inflammatory and
repair process implicated in atherogenesis (9, 10). Generation of mice deficient
in CD47 (discussed below) shows the importance of signaling through its MØ-
expressed ligand, CD172a, in suppressing inappropriate self-phagocytosis. The
recent generation of mannose receptor (MR)–deficient mice has demonstrated the
importance of this receptor in the maintenance of normal levels of endogenous
glycoproteins and clearance of lysosomal hydrolases during steady state and in-
flammatory conditions (see MØ C-type lectins).
MØ are present in large numbers at portals of entry from the outside envi-
ronment, for example within the lungs, which are constantly exposed to foreign
particles, viruses, bacteria, and fungi. Alveolar MØ express high levels of PRR
including scavenger receptors (SR), MR, and the β-glucan specific receptor,
Figure 1 Phenotypic heterogeneity of monocytes/MØ and DCs during differentiation

in vivo. Circulating monocytes that give rise to resident- and inflammatory-type elicited
MØ already display a distinct phenotype, as do MØ and DCs in different tissue microen-
vironments. Differentiation antigens and membrane receptors are described subsequently in
this review. Antigens listed in brackets correspond to human receptors; all other antigens
refer to studies of murine cells.
Dectin-1. In such a relatively opsonin-poor environment, the expression of spe-

cific receptors for the direct recognition and uptake of microbes could play an
important role in innate host defense. Exposure of MØ to microbial products and
cell-derived cytokines such as IFN-γ and IL-4, in vitro and in vivo, has been
shown to induce different activation states in these cells, adding to further het-
erogeneity (11) (Table 2). These stimuli modulate surface receptor expression,
secretory and antimicrobial activities, antigen presentation and costimulation, and
antigen-specific lymphocyte responses.
MØ HETEROGENEITY AND THE SPLEEN

The rodent spleen is an example of heterogeneity that underlies the potential diver-
sity of immune recognition by MØ (Figure 2). The spleen is rich in subpopulations
of MØ that differ in receptor expression, microanatomical location, life history,
906 TAYLOR ET AL.
TABLE 2 Macrophage activation: heterogeneity of phenotypea

Innate activation Classical activation Alternative activation
Neisseria
Stimuli meningitidisb IFN-γ IL-4/13
Effects on ↑ MARCO ↑ MHC class II ↑ MR

surface ↑ CD200 ↑ CD86 ↑ Dectin-1
antigens ↑ Co-stimulatory ↓ MR ↑ CD23
antigens (synergy ↓ CD14
with IFN-γ ) CD163
Metabolic ↑ iNOS ↑ iNOS ↑ Arginase
changes Respiratory burst Respiratory burst
Secretory Synergy with Pro-inflammatory IL-1RA
responses IFN-γ -induced cytokine and IL-10
responses chemokines Chemokines
(TNFα, IL-12, IL-1, (e.g., AMAC-1)
IL-6, IP-10, MIP-1α, Chitinase-like proteins
MCP-1) (Ym1/2)
and low MW mediators
Functional Phagocytosis ↑ Antigen presentation ↑ Fibronectin and matrix
effects of (by regulation of ↑ Killing of associated proteins.
activation receptors) intracellular pathogens Promotes cell growth,
Pro-inflammatory Pro-inflammatory collagen formation, and
signaling via TLR tissue repair.
Enhanced ↑Humoral/allergic
costimulatory immunity
antigen expression ↑Parasite killing
a
MØ display a spectrum of distinct phenotypes associated with different forms of immune activation.
b
N. meningitidis is given as an example of a direct Gram-negative microbial stimulus based on Reference 15 and unpublished
observations by S. Mukhopadhyay.
and function. Individual receptors are described below. Red pulp MØ in the spleen,
expressing high levels of the F4/80 antigen and the MR, include stromal-type MØ
involved in hemopoiesis and are extensively involved in the clearance of senescent
erythrocytes. In the marginal zone (MZ) of the spleen, which is notably lacking
in F4/80 expression, two MØ populations are present within a complex mix of
fibroblasts, endothelia, DCs, and subpopulations of lymphocytes. The MZ repre-
sents the interface of splenic lymphoid tissue and the circulation (12). Sialoadhesin
high-expressing metallophilic MØ are found in the inner layer of the MZ adjacent
to the white pulp. The existence of the metallophilic MØ is dependent on M-CSF
and members of the TNF (tumor necrosis factor) receptor family, and although
their function in the evolution of an immune response is still poorly understood,
they appear to play a role in the initial response to systemic infection. Phago-
cytic marginal zone MØ (MZMØ) are found in the outer marginal zone. MZMØ
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MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION
Figure 2 Heterogeneity of MØ subpopulations in mouse spleen, illustrated by use of differentiation and receptor antigens. The immunohis-
tochemical images show clear heterogeneity of expression of F4/80, MARCO, and Sialoadhesin, exhibited by red pulp, MZ, and metallophilic
907
MØ. Schematic diagram based on G. Kraal (12).

908 TAYLOR ET AL.
express an array of PRR including the scavenger receptor-A (SR-A), macrophage

receptor collagenous domain (MARCO), and SIGN-related 1 (SIGNR1). These
receptors allow the MZMØ to recognize and interact with soluble and particulate
antigens and microorganisms within the circulation. MØ are also present within
the splenic white pulp, including tingible body MØ, which phagocytose apoptotic
B cells generated during germinal center reactions. These white pulp MØ express
the pan MØ antigen CD68, but lack other MØ markers such as F4/80.
SCAVENGER RECEPTORS AND MICROBIAL

RECOGNITION
SR-A I/II
Historically, the identification of SR-A (I,II) (referred to here as SR-A) as an
important nonopsonic receptor for modified low density lipoproteins, acetylated
LDL, and other selected polyanions including lipid A, drew attention to its possible
role in foam cell formation and atherogenesis (13) as well as host defense (9). It was
the first collagenous transmembrane receptor to be cloned, and its cysteine-rich
domain (SRCR) found in the SR-A I isoform became the prototype for the presence
of similar domains in a range of immune cell adhesion molecules expressed by
lymphoid as well as myeloid cells (Figure 3). The SR-A ligand-binding site for
polyanionic ligands is thought to be associated with the collagenous domain. In the
case of CD163, a MØ-restricted endocytic receptor for hemoglobin-haptoglobin
complexes, multiple SRCR domains are likely to be responsible for ligand binding
(14).
The molecular cell biology of SR-A has been extensively reviewed (9, 15). We
emphasize microbial recognition here, and below we consider its role in apoptotic
cell clearance. The molecule is well expressed at the surface of MØ and subpopu-
lations of DC, but not monocytes or PMN; selected endothelia also express SR-A.
A large part of SR-A expression is intracellular, within the endocytic compartment.
Studies by Peiser et al. (16) showed that select bacteria were taken up via SR-A;
this was demonstrated in phagocytosis assays with bone marrow culture–derived
MØ (BMDM) from wild-type and knockout mice. These cells express high lev-
els of receptor owing to upregulation by M-CSF present in the culture medium.
Peritoneal exudate MØ express lower levels of SR-A, as well as additional SR.
Neisseria meningitidis (virulent and nonvirulent strains) express microbial lig-
ands for nonopsonic uptake via SR-A. The phagocytic ligand is independent of
lipid A, which is required for the induction of proinflammatory cytokine secre-
tion. Unpublished studies have identified novel protein ligands, concentrated in
outer membrane vesicles, that are bound and endocytosed via SR-A (L. Peiser,
unpublished results).
Several studies with wild-type and knockout mice have implicated SR-A in
microbial resistance/susceptibility to bacterial infection in vivo including Listeria
Figure 3 Selected scavenger and functionally related receptors expressed by MØ. Several
have been implicated in binding of G+ and G− bacteria as well as uptake of polyanionic
ligands (acetylated LDL) and in the uptake of apoptotic cells. CD163 contains multiple
SRCR domains and binds hemoglobin-haptoglobin complexes.
monocytogenes and Staphylococcus aureus (17). In other models, prior BCG in-
fection was used to activate MØ in vivo, sensitizing the mouse to LPS challenge.
SR-A protects the animal against systemic TNF release and septic shock. Table 3
summarizes phenotypic changes derived from genetic ablation of SR-A and other
MØ-expressed receptors/ligands.
MARCO
MARCO is a MØ- and DC-restricted SR-A family member that resembles SR-A,
but it is the product of a distinct gene, and its expression pattern is very differ-
ent (18). It is constitutively present on MZ and some, but not most, tissue MØ,
and it is readily induced by microbial and other stimuli, acting through various
TLR. It is predominantly expressed at the cell surface, mediating adhesion to
substrata and ingestion of particulates such as titanium dioxide by alveolar MØ.
910 TAYLOR ET AL.
TABLE 3 Phenotypes derived from receptor/ligand knockouts

Receptor Knockout MØ phenotype summary
Scavenger and related

SR-A Impaired clearance of modified LDL. Impaired phagocytosis
of apoptotic cells (in vitro) and select microorganisms. Altered
susceptibility to endotoxic shock and atherosclerosis
CD36 Effects on clearance of apoptotic cells, atherogenesis and resistance
to select bacteria
CD14 Impaired responses to endotoxin and altered responses to infection
PSR Neonatal lethal, defective fetal liver erythropoiesis, variable effects
on development and clearance of apoptotic cells
Integrins
CD11b Altered myeloid cell recruitment in inflammation and impaired
complement-opsonized phagocytosis
Ig Superfamily
‘TREM2’ DAP12-deficient mice have Nasu-Hakola-like disease symptoms similar
to DAP12/TREM2-deficient humans
Symptoms: presenile dementia and bone cysts
‘CD200R’ CD200-deficient mice exhibit enhanced MØ activation leading to an
increase in severity of inflammatory diseases
‘SIRPα’ Phagocytosis of CD47-deficient erythrocytes is not inhibited via SIRPα.
CD47-SIRPα also regulates Fc and complement-mediated
phagocytosis
‘M-CSFR’ Osteopetrotic phenotype in mice with a natural mutation in M-CSF.
Reduced numbers of monocytes and selected MØ including osteoclasts
Siglec-1 Siglec-1-deficient MØ exhibit a significant defect in Neisseria binding
(in vitro).
Siglec-3 Mice are viable and fertile. No obvious phenotype described
PIRB Impaired DC maturation with enhanced Th2 responses. Increased
graft-versus-host disease
C-type-lectin-like
CD69 Alterated B cell development. Enhanced antitumor response. Enhanced
autoimmune reactivity and inflammation in experimental arthritis.
C-type Lectins
Mannose receptor Impaired clearance of select, endogenous glycoproteins. Also reported
as a lethal phenotype owing to abnormal lutropin clearance.
Apparently normal control of fungal infection.
Endo180 Defect in collagen binding and internalization.
Non-phagocytic ligands have also been reported on B lymphocytes, which may

traffic through the MZ (19). Although the polyanion-sensitive binding properties
of this SR remain poorly defined, MARCO is known to bind a range of Gram-
positive and Gram-negative bacteria, contributing to localization and clearance of
circulating organisms in the MZ.
CD36
CD36 is a double-spanning SR (Figure 3) with a very different structure from SR-
A. It is related to other SR-B molecules (20) and is thought to be associated with
lipid rafts. An evolutionarily related molecule, Croquemort, is found in Drosophila
(21). CD36 is expressed on monocytes, MØ, platelets, and selected endothelia and
is best known as a SR for oxidized LDL and apoptotic cells (see below).
The role of CD36 in innate immunity was overlooked until recently, when
it turned out to be the genetic target in an ENU mutagenesis program, respon-
sible for a novel TLR-associated phenotype termed “oblivious” (K. Hoebe and
B. Beutler, personal communication). Its ligand was shown to be diacyl fatty acids
found in microbial walls. CD36-deficient mice are susceptible to “spontaneous”
eye infections by Gram-positive organisms. CD36 has also been implicated in
cytoadherence of Plasmodium falciparum.
Lectin-like oxidized low density lipoprotein receptor (LOX-1) (Figure 3) and
other newly described SR expressed by MØ and endothelium have been reported
to bind bacteria (see Supplemental Material). These and other bacterial binding
receptors, e.g., CD14, expressed by MØ are considered further below. Other re-
ceptors for PGN present in both Gram-positive and Gram-negative bacteria have
been described in vertebrates and Drosophila (22).
Although a range of bacterial recognition receptors is now known, their micro-
bial ligands remain uncharacterized, with the exception of CD36. Ligand expres-
sion by different organisms varies greatly and multiple MØ receptors are likely to
collaborate in binding of whole bacteria and in signal transduction.
RECOGNITION OF APOPTOTIC CELLS BY MØ

Apoptosis is a natural process during development, the induction of an adap-
tive immune response and the resolution of inflammation. The onset of apoptosis
in vivo is accompanied by rapid clearance of effete cells by both professional and
nonprofessional phagocytes. In a normal animal, this process is extremely efficient,
and it is difficult to detect apoptotic bodies that are not associated with phagocytes
in tissues. This process may be more than just “waste disposal;” the phagocytosis
of apoptotic cells by MØ results in the production of anti-inflammatory mediators
(23), and the failure to clear apoptotic cells efficiently may lead to exacerbation
of inflammation and a predisposition to the development of autoimmunity (24).
Recently, attention has therefore turned to the recognition mechanisms used by
912 TAYLOR ET AL.
MØ and the identification of multiple candidate receptors (25, 26). Although to

date only a few of these candidates have been shown to play a physiological role in
this process in vivo, this may reflect a lack of study as well as receptor redundancy.
Vitronectin Receptor (αvβ3-integrin)

The first identified receptor for the phagocytosis of apoptotic leukocytes was the vit-
ronectin receptor (VnR, αvβ3-integrin) (reviewed by 26). Since its identification,
many other candidate recognition mechanisms have been proposed. Subsequently,
researchers have shown that VnR cooperates with thrombospondin and CD36,
with soluble thrombospondin serving as a bridge able to bind both the apoptotic
leukocyte and phagocyte, possibly via these two receptors.
Phosphatidyl Serine Receptor (PSR)

The phosphatidyl serine receptor (PSR), which recognizes phosphatidyl-L-serine
but not phosphatidyl-D-serine, was first shown to play a role in the clearance of
apoptotic cells by Fadok and colleagues (27). Subsequently, researchers showed
that different populations of MØ were heterogeneous with regard to their depen-
dence on the PSR or VnR. Ultimately the PSR was cloned by phage display using
a mAb raised against PSR on activated MØ, and it conferred phagocytic activity
for apoptotic cells on cells that were not normally phagocytic (28). More recently,
abnormal development and neonatal lethality, associated with impaired clearance
of apoptotic cells, have been reported in PSR-deficient mice (29), and mutation of
the C. elegans homolog of PSR also leads to an in vivo defect in the clearance of
cell corpses (30). The developmental and clearance defects associated with PSR
deficiency may be variable.
Scavenger Receptors
CD36 CD36 has been implicated in the recognition of apoptotic cells in coopera-
tion with thrombospondin and VnR. Further experiments suggest that expression
of CD36 alone in the usually nonphagocytic COS-7 fibroblastic background is
sufficient to confer upon transfectants the capacity to phagocytose apoptotic cells.
The apoptotic cell ligand for CD36 is not defined, but because it also has the ca-
pacity to bind to anionic phospholipids, the recognition of apoptotic cells by CD36
may involve related structures.
SR-A Blockade of SR-A on MØ, or its genetic deletion, has been shown to im-
pair the recognition of apoptotic thymocytes by MØ (31). The observed defect
in apoptotic cell recognition by blockade or deletion of SR-A applies to both
thioglycollate-elicited peritoneal MØ and primary thymic MØ. However, in the
thymus under steady-state conditions or in the context of experimentally increased
apoptotic cell burden, a defect in in vivo apoptotic cell clearance could not be de-
tected, supporting the idea of widespread redundancy within these recognition
systems (17). The ligand on apoptotic cells that is recognized by SR-A is not
known.
CD14 Characterization of a mAb that blocked the recognition of apoptotic cells

by human monocyte-derived MØ led to the identification of CD14 as a candidate
receptor for apoptotic cells (32). Transfection of COS cells with CD14 conferred
upon these cells the capacity to interact with apoptotic cells. CD14 is known to bind
to phospholipids, but investigators have suggested that this is not the mechanism
by which CD14 recognizes apoptotic cells. Furthermore, intracellular adhesion
molecule (ICAM)-3 expressed on the apoptotic cell may function as the ligand for
CD14. CD14 is discussed in more detail later.
LOX-1 CHO cells expressing bovine LOX-1 were able to bind aged erythrocytes
and apoptotic cells, and these interactions were inhibited by known LOX-1 ligands
and PS liposomes (33). Because PS can block these interactions, PS was considered
to be the ligand on the apoptotic cell. Additional functions of LOX-1 are discussed
with other NK-like C-type lectins below.
β2-GPI Receptor
β2-glycoprotein I (β2-GPI) is a plasma protein that can bind to exposed PS on the
surface of apoptotic cells. It forms a bridge between the apoptotic cell and MØ
via an unidentified receptor (34). The requirement for the plasma protein in this
process was shown by blockade with β2-GPI specific F(ab)2 fragments, which
blocked enhanced uptake by MØ, and MØ association with β 2 -GPI could only
occur after prior recognition of PS.
Complement Receptors 3 and 4 (CR3 and CR4)

Korb and Ahearn reported a possible role for complement in the recognition of
apoptotic cells when they observed binding of C1q to apoptotic cells (reviewed by
24). A role for complement receptors in the clearance of apoptotic cells was first
demonstrated by the identification of heat labile components of serum, which en-
hanced apoptotic cell binding to MØ. Serum-depletion studies implicated both the
classical and alternative pathways of complement, and antibody blockade showed
that CR3 and CR4 played a role in the clearance of opsonised apoptotic cells by
human MØ. The recognition of apoptotic cells by CR3 and CR4 depends on prior
opsonization, unlike most of the receptors discussed in this review. A role for the
classical pathway of complement in the clearance of apoptotic cells was verified
in mice using a novel in vivo clearance model.
CD91-Calreticulin Recognition of C1q, SP-A, and SP-D

After the initial observation that C1q could bind directly to apoptotic cells and
the suggestion that CR3 and CR4 play a major role as MØ receptors for apoptotic
914 TAYLOR ET AL.
cell recognition, investigations in mice led to the discovery of a differential im-

portance of the classical pathway complement components in the clearance of
apoptotic cells. C1q-deficient mice displayed a more profound defect in apoptotic
cell clearance than C4-deficient mice, and more apoptotic bodies were present
in the kidneys of disease-free C1q-deficient mice. A C1q receptor may play ad-
ditional roles in apoptotic cell recognition to those receptors that recognized C3
activation fragments, perhaps by direct recognition through C1q receptors. Ogden
and colleagues (35) identified calreticulin (also known as cC1qR) in a complex
with the endocytic receptor CD91 (α-2-macroglobulin receptor) as the surface re-
ceptor for C1q. They showed that the structurally similar mannose-binding lectin
(MBL) was able to facilitate apoptotic cell clearance via the same surface receptor
complex.
Surfactant proteins A (SP-A) and D (SP-D) have also been implicated in recog-
nition of apoptotic cells. The addition of either SP-A or -D to in vitro assays
with isolated alveolar MØ leads to enhancement of phagocytosis of apoptotic neu-
trophils (36). Like C1q and MBL, both SP-A and -D were able to bind to MØ via
the calreticulin:CD91 receptor complex (37). Furthermore, in clearance studies,
SP-D affected the clearance of apoptotic cells in vivo.
MER and Gas6

Gas6 (growth arrest specific gene 6) is a ligand of the receptor tyrosine kinases
Axl, Sky, and Mer. Gas6 exhibits Ca2+ -dependent binding to PS (38) and PS-
containing liposomes, suggesting that Gas6 may function as a bridge between
the apoptotic cell and MØ. Scott and colleagues (39) genetically deleted MER, a
member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. The MER-deficient
mouse exhibited in vivo defects in the clearance of apoptotic cells, and in vitro
MØ showed a marked impairment in their ability to internalize apoptotic cells.
Annexins
Because of the recognized role of annexins in binding to PS, Fan et al. (40) investi-
gated the role of annexins I and II in the recognition of apoptotic cells by MØ. Not
only is PS exposed on the surface of apoptotic cells, but its exposure on the surface
of the phagocyte is also required for the recognition of apoptotic cells. Annexins I
and II differ from the other annexins in that they are able to aggregate liposomes
and therefore may simultaneously bind apoptotic cell– and phagocyte-exposed
PS. Blockade of annexins I and II with mAbs impaired apoptotic cell recognition
in vitro.
SEVEN TRANSMEMBRANE RECEPTORS

The seven-span membrane (TM7) receptors are the largest superfamily of cell-
surface receptors, comprising >1% of the functional genes within the human
genome. Found on all cell types including MØ, TM7 molecules transduce signals
for an array of stimuli, including microbial products, peptides and amino acid
derivatives, lipid analogues, ions, and external sensory stimuli such as light, taste,
and odors, via classical G protein–coupled pathways. In addition to these signaling
pathways, a variety of G protein–independent mechanisms have begun to emerge.
Receptors for chemokines, including C5a and formyl peptide, have been reviewed
extensively. Here we describe a subfamily of surface TM7 with large extracellular
domains with putative adhesion and signaling functions in MØ.
The EGF-M7 Family

The human EGF-TM7 family comprises CD97, EGF-module-containing mucin-
like hormone receptor (EMR) 1, EMR2, EMR3, and EMR4 (41) (Figure 4). These
predominantly leukocyte-restricted glycoproteins are defined by their unusual hy-
brid structure, which consists of a large extracellular domain containing vary-
ing numbers of epidermal growth factor (EGF)-like repeats coupled to a family
B GPCR (G protein–coupled receptor)-related moiety via a region containing a
GPCR proteolytic site (GPS). The majority of the genes have been shown to ex-
press multiple protein isoforms possessing various numbers and arrangement of
their extracellular EGF domains. As similar EGF domains mediate protein-protein
interactions in numerous other proteins and TM7 domains have the obvious po-
tential to signal, it has long been proposed that EGF-TM7 receptors may couple
extracellular recognition events to intracellular signaling in leukocytes. Extracel-
lular ligands have been identified for several of the receptors, and roles in myeloid
recognition and migration have been demonstrated. The EGF-TM7 receptors are
not present in invertebrates, but they have been identified in a number of verte-
brates (41). These findings, together with the absence of mouse EMR2 and EMR3
orthologs, indicate a relatively recent and rapid evolution, a phenomenon often
found within the immune genes.
EMR1 (F4/80) EMR1 possesses six EGF domains linked to a TM7 region; so far,
expression data for the human molecule are restricted to RT-PCR, but results
indicate high levels of expression on blood monocytes and MØ cell lines. EMR1
shows 68% homology to its murine ortholog F4/80. F4/80 has long been used
as a specific marker for populations of mouse tissue MØ. F4/80 is present in the
liver (Kupffer cells), lamina propria (gut), splenic red pulp, lymph nodes (medulla),
brain (microglia), bone marrow stroma, and Langerhans cells in the skin (Figure 1).
F4/80 is downregulated upon stimulation of Langerhans cells as they migrate to
the draining lymph nodes and is absent in T cell areas of the spleen and lymph
nodes, indicating a possible role in the retention/adhesion of MØ in specific tissue
areas. F4/80 is also expressed by eosinophils and some DCs. Although F4/80
knockout mice do not exhibit any gross phenotype or aberrant MØ populations
(42), antibody blocking studies have implicated F4/80 in MØ-dependent IFN-γ
release from NK cells in response to Listeria and in peripheral tolerance (43, 44).
Recent data obtained using F4/80-deficient mice in models of oral tolerance and
21 Dec 2004
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TAYLOR ET AL.
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Figure 4 The EGF-TM7 receptors expressed by MØ and other myeloid cells. ∗ The ortholog of EMR4 in human contains a deletion that
results in a premature stop codon.
anterior chamber-associated immune deviation have demonstrated a role for F4/80

in tolerance (H-H. Lin, unpublished data).
EMR2 EMR2 is highly expressed on PMNs and certain tissue MØ and to a lesser
extent on peripheral monocytes (45). Ligand-binding studies have shown that the
largest EMR2 isoform containing five EGF domains binds specifically to a re-
stricted population of chondroitin sulphate B species found in tissues and expressed
by B cells, facilitating cell attachment in vitro (46; M. Kwakkenbos, unpublished
data). As glycosaminoglycan populations are known to alter during inflammation
and wound repair, chondroitin sulphate recognition by EMR2-expressing MØ and
PMNs may allow the interaction with B cells and retention/migration within tis-
sues. The signaling consequences of chondroitin sulphate binding remain to be
established. Preliminary data suggest EMR2 ligation can result in cellular acti-
vation (M. Stacey, unpublished data). A mouse model is not available because a
murine ortholog to EMR2 does not exist.
CD97 The EGF domains of the full-length CD97 protein are 97.5% identical to
those of EMR2 (41, 45). Like EMR2, various CD97 protein isoforms are expressed,
consisting of different numbers of the EGF domains. However, unlike EMR2,
CD97 has a less restricted expression pattern and is found on B and T cells, smooth
muscle cells, and myeloid cells. The largest 5-domain isoform of CD97 binds to
chondroitin sulphate, whereas a smaller 3-domain isoform of CD97 also recog-
nizes the complement regulatory protein, decay accelerating factor (DAF/CD55)
(see below). The significance of the recognition of CD55 and chondroitin sulphate
remains unclear; recently, mouse studies have shown that CD97 may play a role
in neutrophil migration. In murine sodium dextran sulphate–induced experimental
colitis, treatment with antimouse CD97 antibody delayed homing of neutrophils to
the colon, and in S. pneumoniae–induced pneumonia, it caused a reduced inflam-
matory infiltrate in the lung after 20 h, resulting in diminished survival (47). CD97
expression has been implicated in a number of human autoimmune diseases. In
rheumatoid arthritis, synovial MØ have increased levels of CD97 and are seen to
be in close association with CD55+ fibroblast-like synoviocytes (48; E. Kop, un-
published data). Studies of multiple sclerosis patients showed that although white
matter from healthy tissues express no CD97, microglia and infiltrating MØ and
T cell in MS patients express high levels of CD97. The concomitant upregulation
of CD55 on endothelium in MS (49) may play a role in migration or activation
of CD97+ MØ. Studies of the CD97−/− mouse should shed further light on the
physiological role of CD97.
EMR3 To date, expression data on EMR3 are restricted to RNA analysis. How-
ever, results show that expression is restricted to MØ and neutrophils. Ligand
studies using the two EGF domains from EMR3 have demonstrated the exis-
tence of cognate receptors on culture-derived human MØ and activated neutrophils
(50). Previously, the chromosomal location of EMR3, 19p3.1 has been linked to
Crohn’s disease, a condition associated with aberrant mucosal immune responses
918 TAYLOR ET AL.
characterized by the dense infiltration of MØ and lymphocytes. Recent sequencing

of DNA from more than 1200 patients and 700 healthy individuals has demon-
strated that polymorphisms in the EMR3 gene as well as other EMR family mem-
bers are strongly linked to CD susceptibility (D. Jewell, unpublished data).
EMR4 Mouse EMR4 is predominantly expressed on resident MØ. The expres-

sion of mEMR4 is higher on peritoneal MØ elicited with Biogel and thioglycollate
broth. Similarly, mEMR4 is overexpressed in TNF-α treated resident peritoneal
MØ, whereas IL-4 reduces expression. Antibody staining revealed expression on
populations of DCs. Ligand studies have demonstrated a ligand on the A20 lym-
phoma cell line, suggesting a possible role in the regulation of B cells by MØ and
DCs. The gene encoding human EMR4 appears to be a potential pseudogene or
soluble protein, owing to a deletion that inserts a premature stop codon (51). In-
terestingly, however, the gene is intact in both New and Old World apes, implying
a rapidly evolving gene.
GLYCOSYLPHOSPHATIDYLINOSITOL (GPI)-ANCHORED
MEMBRANE PROTEINS
In addition to using membrane-spanning hydrophobic residues for the association
with plasma membrane, cell surface receptors can also use a phosphatidylinositol-
based glycolipid (GPI) to anchor in cell membranes. As a result of their GPI
anchor, the intracellular sorting and cell surface distribution of the GPI-anchored
proteins is distinct from that of the transmembrane proteins. Thus, GPI-anchored
proteins were found in detergent-resistant fractions located in the sphingolipid
and cholesterol-enriched subdomains (lipid rafts) of cell membranes. These char-
acteristics have been implicated in several important biological functions of GPI-
anchored proteins, including intracellular signaling and receptor-mediated uptake
of pathogens. Although the GPI-anchored proteins are widely expressed, we focus
on two major GPI-anchored receptors that are relevant to immune recognition by
MØ.
CD14
CD14 is mainly expressed on cells of the myeloid lineage, including monocytes,
MØ, and granulocytes, although other cell types such as B cells, liver parenchy-
mal cells, and gingival fibroblasts can also express CD14. With the use of antibody
that prevented binding of LPS-LBP (LPS-binding protein) complex–coated ery-
throcytes to MØ, CD14 was identified more than a decade ago as a receptor for LPS
(52). Furthermore, expression of CD14 on CD14-negative cells rendered cells re-
sponsive to LPS (53). Over the years, other microbial and endogenous ligands were
identified for CD14, such as LTA (lipoteichoic acid), PGN, and apoptotic cells (54).
Because CD14 does not contain a transmembrane domain (Figure 3), accessory
molecules are needed for signal transduction. In recent years, TLR4 and TLR2
were identified as coreceptors with CD14 for specific microbial ligands (55). The
extracellular domain of CD14 contains 10 leucine-rich motifs (56). The N-terminal
portion of the CD14 is important for LPS binding and the interaction with accessory
receptors (57).
In addition to the membrane-bound form, a soluble form of CD14 (sCD14) was
first observed in monocytes as the MY-4 antigen (58). TNF-α and LPS induce the
release of sCD14, whereas IFN-γ and IL-4 inhibit it. In patients with septic shock,
the level of sCD14 in serum was increased substantially, and the levels of sCD14
correlate with mortality (59).
CD55
Also named decay accelerating factor (DAF), CD55 is a complement regulatory
protein that protects cells from complement-mediated attack (60). It enhances the
decay of the C3/C5 convertases formed in the alternative and classical pathways of
complement activation. CD55 is expressed on all cells exposed to plasma, including
cells of hemopoietic and nonhemopoietic origins. In addition to interaction with
the convertases, CD55 has been used as a cellular receptor by a range of viral
and bacterial pathogens (61). Anti-CD55 antibody inhibits the binding of several
echoviruses to susceptible cells (62), and transfection of CD55 in nonsusceptible
cells enabled cells to bind viruses efficiently (63). CD55 is also a receptor for
bacterial fimbriae and other adhesins (64–67).
CD55 belongs to the RCA (receptor of complement activation) family and
contains four protein short consensus repeat (SCR) modules in the extracellular
domain (60, 68). Detailed structural-functional studies, along with genetically
engineered mutants and specific mAbs to distinct SCRs, have located most of the
binding sites for individual viral and bacterial ligands. Different SCRs were used
as binding sites for different but closely related viruses. Furthermore, most of the
virus- and bacteria-binding sites are located in SCR2-4 that are also important for
complement regulation (69).
In the past decade, CD97, a member of the EGF-TM7 receptor family, was
identified as an endogenous cellular ligand for CD55 (70). Like most of the cell
surface protein-protein interaction on leukocytes, the CD55-CD97 interaction is of
low affinity (KD of 86 µM) (71). More recently, an anti-adhesive function of CD55
in human neutrophil transmigration across mucosal epithelia has been reported,
although the reciprocal cellular ligand for CD55 was not identified (72).
MEMBERS OF THE IMMUNOGLOBULIN

SUPERFAMILY (IgSF)
MØ express important IgSF, such as various FcR and the receptor for M-CSF.
These have been extensively reviewed elsewhere. Here we summarize data on a
variety of other molecules implicated in MØ recognition (Figure 5).
920 TAYLOR ET AL.
Figure 5 Selected IgSF glycoproteins expressed by MØ. Some receptors contain ITIM
sequences in their cytoplasmic tails, which mediate inhibitory signals. TREM1 and TREM2
have charged residues in their transmembrane domains, which allow association with the
ITAM-containing DAP12.
Triggering Receptors Expressed by Myeloid Cells (TREMs)

The TREM family of molecules consists of four myeloid transmembrane glycopro-
tein receptors. Little is known about the inhibitory receptor (TREM-like transcript
1, TLT1), other than that it contains an immunoreceptor tyrosine-based inhibition
motif (ITIM) domain that when phosphorylated recruits SH2-domain-containing
protein tyrosine phosphatase 1 (SHP1) (73). The activatory receptors TREM1 and
TREM2 are functionally better characterized and are described below. A third re-
ceptor of unknown function (TREM3) also appears to be an activatory receptor,
although in humans it may be a pseudogene.
TREM1 TREM1 is expressed by monocytes/MØ and neutrophils and associates

with the immunoreceptor tyrosine-based activation motif (ITAM)-containing sig-
naling molecule DAP12 (74). The use of mAb against TREM1 highlights the
potential importance of TREM1 in inflammation as it induces the expression of
IL-8, monocyte chemoattractant protein 1 (MCP1, CCL2), MCP3, and macrophage
inflammatory protein 1α (MIP1α) (75). Anti-TREM1 mAb also enhances LPS-

induced TNFα production by monocytes and stimulates myeloperoxidase release
by granulocytes. The potential role of TREM1 as an amplifier of inflammation has
been confirmed in vivo by blockade of its natural ligand interaction with a soluble
recombinant TREM1-Fc chimeric protein. Blockade of TREM1 in vivo prevents
shock and death in septic shock models, which use live E. coli or cecal ligation
and puncture (76).
TREM2 Whereas TREM1 appears to act mainly through regulating the activation
of monocytes and granulocytes, TREM2 acts on other myeloid cells (DCs, osteo-
clasts, and microglia). In humans, TREM2 is expressed by monocyte-derived DC,
and mAb against TREM2 induces a partial maturation state in which CCR7, MHC
class II, and the costimulatory molecule CD86 were upregulated (73).
A role for TREM2 in brain and bone function has recently been discovered
as a result of studies of the rare human disease Nasu-Hakola disease (polycys-
tic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), which
is characterized by both presenile dementia and the formation of bone cysts.
Linkage analysis identified mutations in DAP12 in this disease (73), and, inter-
estingly, DAP12-deficient mice have similar features (77). Further analysis of
patients with normal DAP12 expression identified mutations in TREM2. TREM2
and DAP12 are expressed by osteoclasts, and monocytes derived from TREM2-
and DAP12-deficient subjects do not differentiate in vitro into mature osteoclasts,
nor do monocytes from DAP12-deficient mice. Microglia and oligodendrocytes
express TREM2 and DAP12, consistent with the neural phenotype of deficient in-
dividuals. In vitro differentiation of monocytes into DCs appears to be impaired in
TREM2-deficient individuals. Therefore, TREM2/DAP12 expression by myeloid
precursors is required for normal maturation of DCs, osteoclasts, and microglia,
although the mechanism is not clear.
TREM2 has also been reported to have SR-like properties, binding to anionic
carbohydrates on bacteria and yeast, which suggests that TREM2 may play a role
in pathogen recognition (reviewed by 73).
Sialic Acid–Binding Immunoglobulin-like Lectins (Siglecs)

Members of the siglec family expressed on MØ include Siglec-1 (Sialoadhesin),
Siglec-3 (CD33), and Siglec-5. The siglecs are a major group of receptors involved
in the recognition of sialic acid, with individual specificity for particular sialic acid
linkages (78). All siglecs possess an N-terminal V-type Ig domain that binds sialic
acid and between 1 and 16 C2-type Ig domains (Figure 5).
SIGLEC-1 (SIALOADHESIN) Siglec-1, the first identified siglec, is the largest, with
17 Ig domains. It was identified as a nonphagocytic MØ sheep erythrocyte receptor
(79) and is expressed at high levels on specific subsets of MØ, particularly in
lymphoid tissues such as the splenic metallophilic MØ. Siglec-1 is an extended
922 TAYLOR ET AL.
molecule, enabling it to interact with sialic acids without interference from sialic
acids expressed by the same cell. The tightly regulated expression pattern and
ability to bind sialic acids suggests that Siglec-1 may be involved in recognition of
sialic acids on other host cells, as has been shown for granulocytes, as well as on
microbes. Siglec-1−/− MØ display a reduced capacity to bind to Neisseria (80).
SIGLEC-3 (CD33) AND RELATED MOLECULES EXPRESSED BY MØ CD33 is relatively

small, with two Ig-like domains. One way it differs significantly from Siglec-1 is in
the presence in its cytoplasmic tail of two ITIMs. When mAb are used to crosslink
CD33 at the same time as Fcγ RI, the resultant Ca2+ flux is reduced compared with
crosslinking of Fcγ RI alone, suggesting that CD33 could function as an inhibitory
receptor (81). CD33 expressed in transfected cells is unable to rosette erythrocytes
unless the transfected cell is first treated with sialidase to remove sialic acids that
mask its binding potential. The existence of a series of CD33-related siglecs ex-
pressed by monocyte and MØ (Siglecs-5, -7, -9, -10, -11) (82) has clouded the
issue of which receptors in mouse and human are the functional equivalents, and
this can only be resolved by comparative expression and ligand binding assays.
With this in mind, a CD33-deficient mouse has been generated, which currently has
no ascribed phenotype (83); however, there are clear differences between human
and mouse CD33, such as the lack of ITIMs in the murine molecule. Although
the binding profiles of at least the human versions of the CD33-related siglecs
are beginning to be characterized, there is little information so far regarding their
physiological roles.
The ILT/LIR/MIR Family of Receptors

A family of receptors has acquired the names Ig-like transcripts (ILTs), mono-
cyte/MØ Ig-like receptors (MIRs), and leukocyte Ig-like receptors (LIRs) (re-
viewed by 84). This family is genetically and functionally related to the killer cell
Ig-like receptors (KIRs), which are a group of NK (natural killer) cell receptors
for HLA class I molecules. ILT/MIR/LIR isoforms are expressed by myeloid and
lymphoid cells, and some of the family members recognize HLA class I. One
subset of this family (ILT2, 3, 4, 5 and LIR8) contains ITIMs and inhibits cellular
activation via recruitment of SHP1. Other members of the family (ILT1, ILT1-like
protein, ILT7, ILT8 and LIR6a) associate with the ITAM-containing FcR common
γ -chain to transmit activatory signals into the cell. ILT6 does not fall into either
of these subsets; it is expressed as a soluble molecule with no transmembrane or
cytoplasmic domains.
Members of the ILT family are expressed by monocytes, MØ, and DCs (among
others). ILT2 and ILT4 both recognize HLA class I molecules, as well as the
trophoblast-expressed nonclassical class I molecule HLAG1 and the virally en-
coded class I–like molecule UL-18. Both ILT2 and ILT4 are ITIM-containing
molecules. This interaction may suppress leukocyte activity at the maternal-fetal
interface and may be used by viruses to suppress responses to infected cells.
The murine homologs of this family are known as paired Ig-like receptors
(PIRs). Although the family structure is different between man and mouse, the
study of the murine PIR family has provided some insights into the function of the
family. Only one member of the PIR family, PIRB, contains ITIMs and mediates
inhibition of cellular functions; the other family members (PIRAs) associate with
the γ -chain. The PIRs are expressed by cells of the monocyte/MØ/DC lineages,
granulocytes, and B cells. PIRB may be constitutively phosphorylated and may
associate with SHP1, possibly as a consequence of direct interaction with MHC
class I (85). Deletion of the inhibitory receptor PIRB in mice in vivo leads to
impaired DC maturation, increased Th2 responses (86), and enhanced graft-versus-
host disease (87).
OX2 (CD200) Receptor (CD200R)

CD200 (OX2) was first identified by the generation of a mAb that revealed ex-
pression by a variety of cells, including thymocytes, B cells, activated T cells,
neurons, and endothelial cells, but not resting MØ (reviewed by 88). CD200 con-
tains two Ig domains and a single transmembrane region. A low-affinity receptor
(CD200R) was identified, which was phylogenetically related to CD200 and genet-
ically linked. Like CD200, CD200R contains two Ig domains; however, CD200R
has a larger cytoplasmic domain that contains tyrosines that can be phosphory-
lated, suggesting that CD200R may transmit an intracellular signal (Figure 5).
The expression of CD200R is largely restricted to cells of the monocyte/MØ/DC
lineages.
The generation of CD200-deficient mice provided the first evidence of the
in vivo physiological role of CD200-CD200R interactions (89). Naive CD200-
deficient mice are relatively normal, and only slightly increased numbers of some
MØ and abnormal mesenteric lymph node organization were reported. However,
after immunological challenge, such as experimental allergic encephalomyelitis
(EAE), altered responses were evident in CD200-deficient mice. EAE could be
readily induced in the CD200-deficient mice, whereas the background C57BL/6
strain is not normally very susceptible; the onset of disease was also more rapid and
the lesions contained more MØ. Similarly, in a model of facial nerve transection,
CD200R-expressing microglia exhibit greater activation in the CD200-deficient
mice, presumably as a result of the loss of a negative signal from the CD200
expressing neurons.
These results have been verified in normal mice using CD200-Fc and
CD200R-Fc fusion proteins. The CD200R-Fc prevents ligation of endogenous
CD200R by blocking CD200, leading to enhanced myeloid cell activity after im-
munological challenge. Conversely, administration of CD200-Fc seems to induce
a negative signal suppressing myeloid cell activity.
CD200R may associate with SH2-containing inositol phosphatase (SHIP), con-
sistent with its apparent role in the downregulation of myeloid cell activity. Thus, a
model has been developed in which CD200 expression at the surface of many cell
924 TAYLOR ET AL.
types enables interaction with CD200R on myeloid cells, leading to generation of

an inhibitory signal within the myeloid cell, which limits cellular activation.
SIRPα (CD172a)
SIRPα (CD172a), like CD200R, is largely restricted to myeloid cells, whereas its
ligand CD47 is more broadly expressed, including on myeloid cells. CD172a con-
tains three extracellular Ig-like domains; its intracellular domain contains several
tyrosines and has been shown to interact with the tyrosine phosphatases SHP1
and SHP2. This inhibits MØ activation, such as response to growth factors or
phagocytosis via Fc or complement receptors (90, 91).
CD200 is unlikely to be a signaling molecule because it possesses a short
cytoplasmic domain with no obvious signaling motifs, and it transmits its negative
signal to myeloid cells via the signaling CD200R. CD47, however, is a more
complicated ligand for the inhibitory CD172a; it also functions as a receptor for
thrombospondin family members and is a component of a complex containing
integrins, heteromeric G proteins, and cholesterol (92).
CD47 has a single N-terminal IgV-like domain, five transmembrane domains,
and an alternatively spliced intracellular domain. The Ig-like domain is required
for interaction with CD172a. Expression of CD47 on erythrocytes functions as a
signal of “self” to MØ by ligation of CD172a, which inhibits phagocytosis (93).
As a consequence, CD47-deficient erythrocytes are rapidly phagocytosed by MØ.
Interestingly, Gardai and colleagues (94) have identified SP-A and -D as ligands
for CD172a. The globular heads of these molecules bind to CD172a, transmitting
an inhibitory signal to alveolar MØ in the lung under steady-state conditions.
However, when alternative surfactant protein ligands such as microbes or dying
cells are present, bound surfactant proteins expose their collagenous domains and
bind to alternative MØ receptors. This provides an interesting model in which
recognition of surfactant protein by CD172a provides a regulatory signal unless
other surfactant protein ligands are present.
NK-LIKE C-TYPE LECTIN RECEPTORS ON MØ

NK-like C-type lectin receptors (NKCL) are type II transmembrane receptors
possessing an extracellular carbohydrate binding domain (CTLD), a stalk region of
variable length, a transmembrane region, and a cytoplasmic tail that may or may not
contain signaling motifs (Figure 6). The CTLD of these receptors shares structural
similarity with the domains found in classical C-type lectin receptors, consisting of
approximately 120 amino acids with at least 3 disulfide bonds, generated through
6 conserved cysteine residues. However, these domains generally lack the residues
involved in calcium binding, which are required for carbohydrate binding in the
classical C-type lectins. Many of these receptors also possess extra cysteines in
their stalk regions, which are involved in homo- or heterodimerization.
Figure 6 Examples of homo- and heterodimerized NKCL receptors and their signaling
motifs. The inhibitory NKCLs possess ITIM sequences in their cytoplasmic tails, whereas the
activatory receptors possess charged residues that allow association with the ITAM-containing
DAP12. Charged residues can also allow association with the PI3K-binding DAP10, thought
to function in costimulation. Dectin-1 is unique in that it is a single chain receptor possessing
its own ITAM-like sequence.
The NKCLs consist of a number of families of highly related receptors that are
often encoded by linked gene clusters, including the NKG2, NKRP1, and Ly49
families, as well as a number of other related molecules, such as CD69, CD94,
Dectin-1, and LOX-1. These genes are mostly located within a single region,
the NK complex, on human chromosome 12 and in a syntenic region on mouse
chromosome 6. While many of the genes in this complex are orthologous, such
as CD69 or CD94, there is significant interspecies diversity in the organization
and complexity of this region. For example, there are 16 Ly49 genes in mouse,
although only one has been identified in human. The structure of these genes is very
similar, with three exons encoding the CRD and one exon for each of the remaining
regions of these receptors. Many of the NKCL genes, such as NKG2D, are also
alternatively spliced, often in a stimulus or cell-type specific manner, resulting in
receptors that can possess different functional abilities.
Many NKCLs, including most members of the NKG2 and Ly49 families, appear
to be expressed exclusively by NK cells and certain subsets of T cells. However,
a limited number have also been identified on other cells, including a related
subgroup that appears to be predominantly expressed in myeloid and endothelial
cells. Expression of NKCLs can be regulated by the stage of cellular differentiation
and activation and by cytokines and other agents. In addition, individual cells may
express different receptor combinations, giving rise to diverse cellular populations.
926 TAYLOR ET AL.
The NKCLs can be broadly categorized as activatory or inhibitory. Most in-

hibitory receptors, such as MICL, possess one or more ITIMs in their cytoplasmic
tails that become tyrosine phosphorylated upon ligation. This leads to the recruit-
ment of phosphatases, such as SHP1 or SHP2, which mediate the downstream in-
hibitory effects. Activatory NKCLs, such as NKG2D, generally lack cytoplasmic
signaling motifs, but they contain charged residues in their transmembrane domains
that allow association with signaling partners, including DAP10 or DAP12. DAP12
contains a cytoplasmic ITAM that induces cellular activation through Syk, whereas
the cytoplasmic tail of DAP10 contains a consensus motif for phosphatidylinositol
3-kinase. Other NKCLs, such as Dectin-1, induce intracellular signals through
unique, and mostly unknown, mechanisms.
The signals generated by the NKCL receptors, especially members of the Ly49,
NKG2, and NKRP1 families, are involved in the regulation of cytotoxicity, through
recognition of MHC class I (or related molecules) or C-type lectin-like receptors.
Others, including those in the subgroup expressed in myeloid and endothelial cells,
appear to have more diverse ligands and cellular functions. However, many NKCLs
are “orphan” receptors with no known functions or ligands. Here we focus in more
detail on those NKCLs that are expressed by MØ and have defined functions, e.g.,
Dectin-1, LOX-1, and CD69. Those receptors expressed by MØ with no known
functions are listed in Table 4 (95–99). Although NKG2D, the subject of review
elsewhere (100), was originally described on MØ, recent evidence suggests that
this molecule is not expressed by these cells (101), and so this receptor is not
discussed further here.
Dectin-1
Murine Dectin-1 was originally isolated as a receptor that recognized an uniden-
tified ligand on T cells, but it was later reidentified as a receptor for β-glucan
polysaccharides (8, 102). Dectin-1 does not appear to oligomerize, but it associates
TABLE 4 Selected orphan NK-like C-type lectins expressed by MØ

Receptor Abbrev. Relevant expression Signaling
Ly49Q Ly49Q Monocytes and MØ ITIM via SHP1/2

Myeloid inhibitory MICL Monocytes and ITIM via SHP1/2
C-type lectin receptor granulocytes
CLEC-1/2 CLEC-1/2 DCs and monocytes Non-typical Tyr-based
motifs
Killer cell lectin-like KLRF1 Monocytes Non-typical Tyr-based
receptor-1 motifs
Myeloid MDL-1 Monocytes, MØ, and Associates with DAP12
DAP12-associating DC
lectin-1
with the tetraspanin receptor CD63, although the functional significance of this
is unclear (103). Dectin-1 is expressed predominantly on myeloid cells, including
MØ and neutrophils, and can be regulated by cytokines and other agents, including
microbial stimuli (102, 104). Human Dectin-1 differs from the mouse receptor in
that it is alternatively spliced, giving rise to a number of different cell-specific
isoforms, of which only two are functional. Dectin-1 recognizes a variety of plant,
bacterial, and fungal β-1,3 and/or β-1,6 glucan-linked carbohydrates, in a Ca2+ -
independent manner, in both soluble and particulate form. This receptor can also
recognize intact fungi such as Saccharomyces cerevisiae, Candida albicans, and
Pneumocystis carinii (102, 105).
Dectin-1 possesses a cytoplasmic ITAM-like sequence that is involved in me-
diating proinflammatory cytokine production in response to β-glucan particles, in
cooperation with TLR2 (106, 107). Dectin-1 can stimulate the oxidative burst in
response to β-glucans, independently of the TLR pathway (106). Dectin-1 is also
a phagocytic receptor, a process mediated by the cytoplasmic motif, but occurring
through a novel, unidentified, Syk-independent pathway (108).
In addition to the exogenous ligands, Dectin-1 recognizes an endogenous ligand
on T cells (102). The receptor can act as a costimulatory molecule, inducing the
proliferation of both CD4+ and CD8+ T cells in vitro, and Dectin-1 expression
has been observed on DCs in T cell areas of the spleen and lymph nodes (109),
consistent with a role in T cell activation. Dectin-1 is present on subpopulations
of MØ and DCs in the medullary and corticomedullary regions of the thymus,
suggesting an additional role in thymocyte development (109). The endogenous
ligand of Dectin-1 has yet to be identified.
LOX-1
LOX-1 (Figure 3) was originally isolated from a bovine aortic endothelial cDNA
expression library screened for receptors for oxidized LDL (OxLDL) (110). LOX-1
is an N-glycosylated dimer that can be cleaved at the membrane proximal region
of the extracellular domain, producing a soluble form whose function is unknown
(111). This receptor is expressed on vascular endothelial cells, platelets, smooth
muscle cells, fibroblasts, and MØ. Expression of LOX-1 can be regulated by a
variety of proinflammatory, oxidative, and mechanical stimuli, and its expression is
upregulated in pathological conditions in vivo, including diabetes, hyperlipidemia,
atherosclerosis, and hypertension.
In addition to recognizing OxLDL, LOX-1 recognizes a variety of other ligands,
including modified lipoproteins, aged/ apoptotic cells, activated platelets, hsp70,
and bacteria (110, 112). The CTLD domain of this receptor mediates the lig-
and recognition, probably through electrostatic interactions of positively charged
residues with negatively charged regions in the ligands, in a manner reminiscent
of other SR.
Although lacking any conserved signaling motif in its cytoplasmic tail, LOX-1
can mediate endocytosis of OxLDL and phagocytosis of aged/apoptotic cells; it
928 TAYLOR ET AL.
modulates cytokine production and induces superoxide anion production, NF-κB

activation, and apoptosis. In addition, LOX-1 acts as a cell-adhesion molecule
involved in leukocyte recruitment in inflammation, and through its interactions
with hsp70, LOX-1 has been implicated in DC-mediated antigen cross-presentation
(112, 113).
LOX-1 is present in atherosclerotic lesions and is thought to play a role in
this disease through its ability to recognize and respond to OxLDL. Although this
receptor can induce pathological changes in endothelial cells, its role in MØ and
the formation of foam cells is unclear.
CD69
Cebrian and colleagues (114) identified CD69, or activation inducer molecule
(AIM), as a marker on lymphocytes that was rapidly induced following cellular ac-
tivation. The receptor is widely expressed on cells of hemopoietic origin, including
neutrophils, monocytes, and MØ, which could be induced by cytokines and various
other agents, including microbial stimuli (115). CD69 is a disulfide-linked, differ-
entially glycosylated homodimer with a typical NKCL structure (116). Although
the physiological ligands for CD69 are unknown, it binds selected carbohydrates
in a novel Ca2+ -dependent manner (117).
CD69 is an activating receptor that has been shown in antibody cross-linking
experiments to induce a wide variety of cellular responses. In monocytes and MØ,
CD69 triggering induced extracellular Ca2+ influx, nitric oxide production, cyto-
toxicity, phospholipase A2 activation, and cytokine production (118). Triggering
of CD69 induced MØ/monocyte apoptosis, in conjunction with LPS, and aided in
the killing of Leishmania in infected MØ. Although lacking any conserved motifs,
the cytoplasmic tail of CD69 can become phosphorylated and, in NK cells, its
cellular functions depend on src-mediated Syk activation (119).
The generation of CD69-deficient mice has given additional insights into the
physiological role of this receptor. Although hemopoietic cell development was
mostly normal in CD69−/− mice, alterations in B cell development were apparent
(120). More recently, these mice have revealed a role for CD69 as a negative
regulator of antitumor responses and of autoimmune reactivity and inflammation,
through induction of TGF-β (121, 122).
CLR
Researchers have identified a family of seven C-type lectin-related (CLRa-g)
molecules that, although similar to the NKCLs, lack at least one of the conserved
cysteines thought to form disulfide bridges in the CRD (123). The various members
of this family have distinct expression patterns in tissues. CLRb is the best studied
and is expressed on most hemopoietic cells, including MØ and DCs, and is reg-
ulated by cytokines and other agents, including calciotropic agents (124). CLRb,
also known as OCIL (osteoclast-derived inhibitory lectin), CLRd (OCILrP1), and
CLRg (OCILrP2), which is also expressed in MØ and DCs (125), are involved in
the regulation of osteoclastogenesis in vitro, although the mechanism is unknown

(126). Despite the unusual CTLD, CLRb can also recognize certain glycosamino-
glycans in a Ca2+ -independent manner (127). Recently, the CLR family of proteins
has been identified as ligands for the NK-specific NKRP1 family of NKCLs. The
interaction between CLR and NKRP1 appears to be specific for each family mem-
ber and results in modulation of NK cell function (124, 125). Although conserved
motifs have been identified in the cytoplasmic tails of the CLRs (126), there is no
evidence of any intracellular signaling.
RECEPTORS IN MACROPHAGES CONTAINING

C-TYPE LECTIN DOMAINS
Receptors included in this section contain C-type lectin-like domains (CTLD) in
which, in addition to a particular protein conformation containing two α-helices
and two antiparallel β-sheets, Ca2+ coordination enables carbohydrate recognition.
Two major groups can be distinguished: type II membrane molecules containing a
single C-type lectin domain and type I receptors with several CTLDs, which have
been generated through domain duplication.
Type II Membrane Receptors Containing a Single

C-Type Lectin Domain
Table 5 lists a range of molecules expressed by MØ in mouse and human (128–
137). Selected receptors are considered in more detail here.
DC-SIGN AND RELATED MOLECULES DC-SIGN is a type II membrane molecule

with a cytoplasmic domain containing an internalization motif, a transmembrane
domain, stalk region, and CTLD (Figure 7). It was first characterized as an HIV
gp120-binding protein, which was able to mediate the LFA-1-independent interac-
tion of DCs with ICAM-3, a molecule highly expressed by naive T cells (134, 135).
DC-SIGN is highly expressed by immature and mature DCs and DCs in the lung,
dermis, mucosal tissue, T cell areas of the tonsil, lymph node, and spleen, as well
as by subpopulations of MØ in the lung (alveolar) and placenta. DC-SIGN binds
ICAM-2, and therefore a role in DC trafficking has been suggested (138). DC-
SIGN functions as an endocytic receptor and enhances antigen internalization and
presentation by DCs to T cells. A related protein with similar functional character-
istics and liver and lymph node–restricted expression has been characterized and
named DC-SIGNR/L-SIGN. Binding to a wide variety of microbes and viruses has
now been demonstrated (e.g., Candida albicans, hepatitis C virus, dengue virus,
Ebola virus, Schistosoma mansoni egg antigens, feline immunodeficiency virus
and alphaviruses, Leishmania, and mycobacterium via recognition of ManLam).
Five DC-SIGN and DC-SIGNR/L-SIGN homologs have been detected in mouse
(139): DC-SIGN (gene located next to CD23, as is human DC-SIGN, and highly
930 TAYLOR ET AL.
TABLE 5 Group II animal lectins in macrophages. Type II membrane receptors containing a

single CTLDa
Protein(s)b Comments Expression
DCAR, DC Associates with Fc receptor γ -chain. RT-PCR: strong in lung and spleen,
immunoactivaing receptor DCAR and DCIR (see below) are weak in skin and LN
considered putative paired BMDC. Exact cellular distribution
immunoreceptors remains to be clarified
DCIR, DC immunoreceptor Functional ITIM Northern blot: PBL > BM, spleen,
(CLECFSF6) and LN
Mo, granulocytes, DC, and B cells
DC-SIGN, DC-specific Endocytic receptor. Ca2+ -dependent Human:
intercellular adhesion recognition of mannose MoDC, MoMØ. DC and MØ
molecule 3-grabbing oligosaccharides on self and nonself: populations in situ
nonintegrin. e.g., ICAM-2 and -3, HIV gp120, Mouse:
Man-LAM, fungi, etc. RT-PCR: CD11c+ DC > B cells
Northern blot:
spleen > lung kidney
Dectin-2, Soluble Dectin-2 prevented UV-induced Northern blot: Spleen and thymus
DC-associated lectin-2 immunosupression, and the induction RT-PCR: mRNA expression in
(CLECSF10/NKCL) of tolerance. May exhibit epidermal cells sensitive to
Ca2+ -dependent mannose binding depletion of MHC class II+ cells
Myeloid progenitors
MCL, MØ C-type lectin Endocytic Mouse:
(CLECSF8) Peritoneal MØ (MØ BM >
spleen = lung > LN
by Northern blot)
Human:
Northern blot: BM, PBL, spleen
RT-PCR: Mo and MØ
MGL1 and 2, MØ pH and Ca2+ -dependent binding to mAb LOM14 mAb recognizes both
galactose/N- α- and β-GalNAc (MGL1) and mouse MGL1 and 2 on tumoricidal
acetylgalactosamine Lewis-X (MGL2). peritoneal MØ, connective tissue
specific C-type lectins 1 Dermal MGL1/2+ MØ migrate to MØ, and BMDC
and 2 draining lymph nodes during the In humans: MGL1 expressed by Mo at
sensitisation phase of contact an intermediate state during their
sensitivity differentiation into MØ immature
MoDC, and cells in human dermis
(90% CD68+ )
Mincle, MØ inducible Expression strongly induced in Elicited peritoneal MØ
C-type lectin (CLECSF9) response to IFN-γ , TNFα, IL-6, and
LPS
SIGNR-1, SIGN-related-1 A murine homolog of DC-SIGNR. Splenic marginal zone MØ
Endocytic receptor. Ca2+ dependent LN medullary and subcapsular sinus
sugar recognition of self and nonself: MØ
e.g., human ICAM-2 and -3, mouse Liver sinusoid endothelial cells
ICAM-2, HIV gp120, mouse ICAM-2,
M. tuberculosis, fungi, etc.
a
Mo, monocyte; MØ, macrophage; MoMØ, monocyte derived MØ (human); MoDC, monocyte derived DC (human); BMDC,
bone marrow derived MØ (mouse); LN, lymph nodes; BM, bone marrow; PBL, peripheral blood leukocytes; RT-PCR, reverse
transcriptase-polymerase chain reaction.
b
Alternate names given in parentheses.
Figure 7 Selected Ca2+ -dependent C-type lectins expressed by MØ. Structural studies with
Endo180 show its CR domain close to the mannose binding CTLD2. It is not known if the
mannose binding CTLD4 of MR exhibits similar juxtaposition to its CR domain. DC-SIGNR
forms tetrameric structures.
expressed in DCs, it is considered the mouse ortholog). Others include SIGNR1,

2, 3, and 4. Mouse DC-SIGN is expressed in spleen and lung and at lower levels in
kidney, heart, thymus, and lymph nodes. Of the other four homologs, attention has
mostly focused on SIGNR1. SIGNR1 is expressed in lymph nodes and at lower
levels in spleen. SIGNR1 has been identified as the antigen on MZ MØ recognized
by mAb ERTR9, a reagent that had previously been shown specifically to label MZ
MØ in spleen and to block binding of neutral polysaccharides (dextran) to the MZ
in vivo (136, 137). Additionally, SIGNR1 has been detected in liver endothelial
sinusoidal cells, but not on Kupffer cells, and in medullary and subcapsular sinus
MØ in lymph nodes. SIGNR1 binds hICAM-2, hICAM-3 and HIV gp-120, and
mouse ICAM-2, and confers on transfected cells the ability to internalize dextran
and bind zymosan and Candida albicans. Recognition of capsular polysaccharide
from S. pneumoniae by SIGNR1 has also been reported both in vivo (using a novel
mAb 22D1 that mediates specific downmodulation of the receptor on MZMØ) and
in vitro (140).
932 TAYLOR ET AL.
DC-ASSOCIATED LECTIN-2 (DECTIN-2) Two groups identified Dectin-2 indepen-

dently: Fernandes et al. (141), through the analysis of genes overexpressed in
a mouse model of chronic myelogenous leukemia blast crisis, and Ariizumi et al.
(142), through a subtractive cDNA cloning strategy for genes selectively expressed
by the DC-like murine cell line XS52, but not by the monocyte-like cells J774.
Dectin-2 is a type II membrane protein with a single C-type lectin domain (which
retains the residues for Ca2+ -dependent carbohydrate binding) on a short stalk, a
transmembrane domain, and a cytoplasmic tail with no obvious signaling motifs.
Dectin-2 is predominantly expressed in spleen and thymus, and RT-PCR analysis of
epidermal cells suggested expression by Langerhans cells. The existence of lectin
activity for Dectin-2 is unclear. Interestingly, Dectin-2 has been implicated in UV
radiation-induced tolerance; administration of soluble bacterial-derived Dectin-2
was able to prevent UV-induced immunosuppression and the induction of tolerance
and apparently restored the antigen response in already tolerized animals (143).
Further work is required to understand the underlying mechanism.
Type I Membrane Receptors Containing Several

C-Type Lectin Domains
The mannose receptor (MR) (CD206) was the first reported member of a family of
four endocytic receptors that share the same overall structure: a cysteine-rich (CR)
domain, a domain-containing fibronectin type II (FNII) repeats and multiple CTLD
in the extracellular region, a transmembrane domain, and a short cytoplasmic tail
(144, 145) (Figure 7). Other members of this family include DEC205 (CD205),
a receptor mostly restricted to DCs that contains 10 CTLD, the Phospholipase
A2 (PLA2 ) receptor, and Endo180, which, together with MR, contains 8 CTLD.
Sequence analysis and sugar binding studies have demonstrated that only MR and
Endo180 contain CTLD that could act as C-type lectin domains. For this reason,
MR and Endo180 will be the only molecules discussed in this review.
MANNOSE RECEPTOR The MR has been identified from different sources as a

175 kDa protein by its selective binding to mannose. The MR is expressed by
most MØ populations, but is also expressed by hepatic and lymphatic endothelia,
mesangial cells in kidneys, tracheal smooth muscle cells, and retinal pigment
epithelium. The MR was first identified because of its suggested role in removal of
lysosomal hydrolases from the circulation (144). It is a recycling receptor present
in the endocytic compartment, and its cytoplasmic tail contains two internalization
motifs. Physiological clearance seems to be a major role of the MR; MR-deficient
mice have increased circulating levels of most lysosomal hydrolases tested, as well
as COOH-terminal propeptide domains of the proalpha 1 and 2 chains of type 1
procollagen and the proalpha 1 chain of type III procollagen (146).
MR recognizes mannose, fucose, and N-acetylglucosamine in a Ca2+ -dependent
manner via CTLD4, with CTLD4-8 sufficient to provide similar high-affinity bind-
ing to the full-length receptor (147). Endogenous ligands for the CTLD of MR
have been described in mouse thyroid gland (thyroglobulin), salivary glands, and
exocrine pancreas (148). Other endogenous ligands for which MR could mediate
clearance are tissue plasminogen activator and neutrophil-derived myeloperoxi-
dase. Glycoprotein hormones from the anterior pituitary are efficiently cleared by
the liver, and a hepatic-specific form of the MR may mediate this uptake (149).
The CR domain of MR is also a lectin and binds to SO4 -4-GalNAc, which is found
in glycoprotein pituitary hormones. This activity may work in conjunction with
the CTLD to facilitate recognition of these hormones by the MR (148). Ligands
for the CR domain (CRL) have been detected on the surface of select MØ sub-
populations in secondary lymphoid organs: MZ metallophilic MØ in spleen and
subcapsular sinus MØ in lymph nodes in naive animals. Further analysis of this
interaction demonstrated binding to cell-specific glycoforms of sialoadhesin and
CD45. The importance of the presence and location of these specific ligands is
unclear, but they appear to label cells involved in the presentation of antigen. These
CRL-expressing cells could potentially interact with a soluble form of the MR (see
below) or with cells expressing MR; however, this requires further study. The FNII
domain is the most conserved domain between the members of the MR family and
is predicted to bind collagen. Although this property has been demonstrated in the
case of PLA2 R and Endo180 (see below), no information is available in regard to
MR.
In addition to the clearance of endogenous glycoproteins, many other functions
have been ascribed to MR. The two best-studied functions are in pathogen recog-
nition and antigen presentation. A wide range of potential microbial ligands has
been reported, such as fungi and viruses (see Supplemental Material), many of
which are also now being reported as ligands for other mannose recognition re-
ceptors such as DC-SIGN. Despite the relatively poor expression observed on DCs
in vivo, DCs in vitro express high levels of the MR and use mannose receptors for
enhanced antigen internalization and presentation. In human lymph node, MR has
been implicated in lymphocyte binding to lymphatic endothelium through a novel
interaction with L-selectin. This interaction may be important for lymphocyte exit
from lymph node.
MR expression is upregulated by IL-4/13 and IL-10 and is downregulated by
IFN-γ . Surface expression is also affected by proteolytic cleavage of the extracel-
lular domain, which generates a functional soluble form of the MR (sMR) that has
been observed in mouse serum.
Endo180 Endo180 is a constitutively recycling endocytic receptor that is pre-

dominantly expressed in vivo and in vitro on fibroblasts, endothelial cells, and
MØ. Dermal CD14+ MØ and cells that resemble Hofbauer cells in placenta
expressed Endo180. Unlike MR, no expression of Endo180 has been observed
in the thymus or in the liver. Like MR, Endo180 binds to mannose, fucose,
and N-acetylglucosamine in a Ca2+ -dependent manner through CTLD2, but not
to galactose (150). Endo180 binds to both native and denatured collagens, and
this binding seems to be mediated by the FNII domain. In cell culture systems,
934 TAYLOR ET AL.
expression of Endo180 results in the rapid uptake of soluble collagens for deliv-
ery to the lysosomal compartments. Endo180 has also been identified as uPARAP
(urokinase-type plasminogen activator receptor associated protein), which forms
a complex on the cell surface with pro-UPA and its receptor (reviewed by 151).
Endo180 is a general promoter of random cell migration and has a more specific
function in cell chemotaxis in a uPA gradient. Endo180 expression enhanced uPA-
mediated filopodia production and promoted rapid activation of Cdc42 and Rac.
Mice have been generated with a targeted deletion in Endo180, which results in a
truncated Endo180 protein that lacks the cysteine-rich domain, the FNII domain,
and CTLD1 (152). Analysis of embryonic fibroblasts revealed that this mutation
did not disrupt the C-type lectin activity mediated by CTLD2 but resulted in cells
with a defect in collagen binding and internalization and an impaired migratory
phenotype.
CONCLUSION
A great deal remains to be learned about the nature, ligands, interactions, and func-
tions of the receptors described in this review. Their ability to discriminate among
different classes of organisms, as well as modified host cells, remains poorly un-
derstood. Microbial specificity of ligand expression is unexplored, and may not fit
with the earlier concept of pattern recognition of conserved structures; neverthe-
less, organisms have diversified, under evolutionary pressure from the innate as
well as the adaptive immune system, and may be able to avoid recognition, e.g., by
masking surface expression of wall constituents. Our knowledge of bacterial and
fungal recognition and sensing is most advanced because their surfaces may be
most foreign. Much less is known about viral recognition, except for host-derived
carbohydrates. Multicellular parasites may also express host molecules on their
surface and have other means to avoid recognition. Modified host components
that are expressed by apoptotic cells are under intense study, but almost nothing
is known about modifications associated with development of tumors, which may
escape surveillance by APC.
The differential responses to exogenous and endogenous ligands (signaling,
gene expression, induction or suppression of acquired immunity) are of great
interest. Considerable progress has been made in the analysis of TLR-adaptor-
NF-κB/interferon pathways, but the question remains: How do the same receptors
generate such different outcomes to truly foreign and abnormal modified host
ligands? These outcomes could be due to different interactions of multi-receptor
complexes at the cell surface, differential expression of receptors by MØ and DCs
(themselves markedly heterogeneous as a result of differentiation), or activation
and responses to their local microenvironments, or they could result from intra-
cellular mechanisms that remain obscure.
The first stage of cataloging receptors and their potential ligands and functions in
immune recognition is well advanced. Integrating this information with studies of
surface expression and secretory and endocytic traffic will require more emphasis
on the cell biology of APC. Interactions of receptors with extracellular matrix and
plasma will further modulate recognition by APC as a fundamental aspect of the
immune response.
APPENDIX
Abbreviations used: APC, antigen-presenting cell; AIM, activation inducer mole-
cule; β 2 GPI, β 2 glycoprotein I; BMDM, bone marrow culture–derived macropha-
ges; CLR, C-type lectin related; CR, cysteine-rich domain of macrophage mannose
receptor; CR3, complement receptor 3; CR4, complement receptor 4; CRD, car-
bohydrate recognition domain; CRL, ligands for the CR domain; CTLD, C-type
lectin carbohydrate-binding domain; CTR, C-type lectin-related receptor; DC-
SIGN, DC-specific integrin grabbing nonintegrin; DAF, decay acceleration factor;
DAP, DNAX activation protein; EAE, experimental autoimmune encephalomyeli-
tis; EGF, epidermal growth factor; EMR, EGF-module containing mucin-like hor-
mone receptor; EMR, EGF mucin containing receptor; FNII, fibronectin type II;
Gas6, growth arrest specific gene 6; GPCR, G protein–coupled receptor; GPI,
glycosylphosphatidylinositol; GPS, GPCR proteolytic site; ICAM, intercellular
adhesion molecule; IgSF, immunoglobulin superfamily; ILT, immunoglobulin-like
transcript; ITAM, immunoreceptor tyrosine-based activation motif; ITIM,
immunoreceptor tyrosine-based inhibitory motif; KIR, killer cell immunoglobulin-
like receptor; LDL, low-density lipoprotein; LIR, leukocyte immunoglobulin-
like receptor; LOX-1, lectin-like oxidized low-density lipoprotein receptor; LPS,
lipopolysaccharide; LTA, lipoteichoic acid; MØ, macrophage; mAb, monoclonal
antibody; MARCO, macrophage receptor with collagenous domain; MBL, mann-
ose-binding lectin; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrop-
hage colony stimulating factor; MIP-1α, macrophage inflammatory protein-1α;
MIR, monocyte/macrophage immunoglobulin-like receptor; MR, mannose re-
ceptor; MZ, marginal zone; NKCL, NK-like C-type lectin-like receptor; OCIL,
osteoclast-derived inhibitory lectin; OxLDL, oxidized LDL; PAMP, pathogen-
associated molecular pattern; PGN, peptidoglycans; PLA2 , phospholipase A2 ;
PMN, polymorphonuclear leukocyte; PIR, paired immunoglobulin-like receptor;
PRR, pattern recognition receptor; PS, phosphatidyl serine; RCA, receptor of com-
plement activation; SCR, short consensus repeat; SHIP, SH2-containing inosi-
tol phosphatase; SHP1, SH2-domain-containing protein tyrosine phosphatase 1;
Siglec, sialic acid–binding immunoglobulin-like lectin; SIGNR1, SIGN-related 1;
SIRP1α, signal regulatory protein 1α; SP-A, surfactant protein A; SP-D, surfac-
tant protein D; SR, scavenger receptor; SRCR, scavenger receptor cysteine-rich
domain; TM7, seven transmembrane; TLT1, TREM-like transcript 1; TLR, Toll-
like receptor; TNF, tumor necrosis factor; TREM, triggering receptor on myeloid
cells; uPARAP, urokinase-type plasminogen activator receptor associated protein;
VnR, vitronectin receptor.
936 TAYLOR ET AL.
ACKNOWLEDGMENTS
We thank colleagues for their contributions, the Medical Research Council (UK),
The Wellcome Trust, Arthritis Research Campaign (UK), British Heart Founda-
tion, and Histiocytosis Association of America for grant support, and Christine
Holt for help in preparing the manuscript.
The Annual Review of Immunology is online at

http://immunol.annualreviews.org
LITERATURE CITED
1. Gordon S. 2003. Macrophages and the 11. Gordon S. 2003. Alternative activation of
immune response. In Fundamental Im- macrophages. Nat. Rev. Immunol. 3:23–
munology, ed. W Paul, pp. 481–95. 35
Philadelphia: Lippincott Raven 12. Kraal G. 1992. Cells in the marginal zone
2. Gordon S. 2002. Pattern recognition re- of the spleen. Int. Rev. Cytol. 132:31–74
ceptors: doubling up for the innate im- 13. Brown MS, Goldstein JL. 1983. Lipopro-
mune response. Cell 111:927–30 tein metabolism in the macrophage: im-
3. Kaufmann SHE, Medzhitov R, Gordon plications for cholesterol deposition in
S, eds. 2004. The Innate Immune Re- atherosclerosis. Annu. Rev. Biochem. 52:
sponse to Infection. Washington, DC: 223–61
ASM Press. 465 pp. 14. Kristiansen M, Graversen JH, Jacobsen C,
4. Akira S, Takeda K, Kaisho T. 2001. Toll- Sonne O, Hoffman HJ, et al. 2001. Identi-
like receptors: critical proteins linking in- fication of the haemoglobin scavenger re-
nate and acquired immunity. Nat. Im- ceptor. Nature 409:198–201
munol. 2:675–80 15. Mukhopadhyay S, Gordon S. 2004. The
5. Inohara N, Nunez G. 2003. NODs: intra- role of scavenger receptors in pattern
cellular proteins involved in inflammation recognition and innate immunity. Im-
and apoptosis. Nat. Rev. Immunol. 3:371– munobiology. In press
82 16. Peiser L, De Winther MP, Makepeace K,
6. Tschopp J, Martinon F, Burns K. 2003. Hollinshead M, Coull P, et al. 2002. The
NALPs: a novel protein family involved class A macrophage scavenger receptor
in inflammation. Nat. Rev. Mol. Cell Biol. is a major pattern recognition receptor
4:95–104 for Neisseria meningitidis which is inde-
7. Janeway CA Jr, Medzhitov R. 2002. pendent of lipopolysaccharide and not re-
Innate immune recognition. Annu. Rev. quired for secretory responses. Infect. Im-
Immunol. 20:197–216 mun. 70:5346–54
8. Brown GD, Gordon S. 2003. Fungal beta- 17. Platt N, Haworth R, Darley L, Gordon
glucans and mammalian immunity. Immu- S. 2002. The many roles of the class A
nity 19:311–15 macrophage scavenger receptor. Int. Rev.
9. Krieger M. 1997. The other side of scav- Cytol. 212:1–40
enger receptors: pattern recognition for 18. Kraal G, van der Laan LJ, Elomaa O,
host defense. Curr. Opin. Lipidol. 8:275– Tryggvason K. 2000. The macrophage re-
80 ceptor MARCO. Microbes Infect. 2:313–
10. Glass CK, Witztum JL. 2001. Atheroscle- 16
rosis. the road ahead. Cell 104:503–16 19. Karlsson MC, Guinamard R, Bolland S,
Sankala M, Steinman RM, Ravetch JV. 2000. A receptor for phosphatidylserine-

2003. Macrophages control the reten- specific clearance of apoptotic cells. Na-
tion and trafficking of B lymphocytes in ture 405:85–90
the splenic marginal zone. J. Exp. Med. 29. Li MO, Sarkisian MR, Mehal WZ, Rakic
198:333–40 P, Flavell RA. 2003. Phosphatidylserine
20. Febbraio M, Hajjar DP, Silverstein RL. receptor is required for clearance of apop-
2001. CD36: a class B scavenger receptor totic cells. Science 302:1560–63
involved in angiogenesis, atherosclerosis, 30. Wang X, Wu YC, Fadok VA, Lee MC,
inflammation, and lipid metabolism. J. Gengyo-Ando K, et al. 2003. Cell corpse
Clin. Invest. 108:785–91 engulfment mediated by C. elegans phos-
21. Franc NC, Dimarcq JL, Lagueux M, phatidylserine receptor through CED-5
Hoffmann J, Ezekowitz RA. 1996. Cro- and CED-12. Science 302:1563–66
quemort, a novel Drosophila hemocyte/ 31. Platt N, Suzuki H, Kurihara Y, Ko-
macrophage receptor that recognizes dama T, Gordon S. 1996. Role for the
apoptotic cells. Immunity 4:431–43 class A macrophage scavenger receptor
22. Rainet M, Pearson A, Baksa K, Harikr- in the phagocytosis of apoptotic thymo-
ishna A. 2003. Pattern recognition on re- cytes in vitro. Proc. Natl. Acad. Sci. USA
ceptors in Drosophila. In Innate Immu- 93:12456–60
nity, ed. RA Ezekowitz, JA Hoffmann, pp. 32. Devitt A, Moffatt OD, Raykundalia C,
127–35. Totona, NJ: Human Capra JD, Simmons DL, Gregory CD.
23. Fadok VA, Bratton DL, Konowal A, 1998. Human CD14 mediates recognition
Freed PW, Westcott JY, Henson PM. and phagocytosis of apoptotic cells. Na-
1998. Macrophages that have ingested ture 392:505–9
apoptotic cells in vitro inhibit proinflam- 33. Oka K, Sawamura T, Kikuta K, Itokawa S,
matory cytokine production through au- Kume N, et al. 1998. Lectin-like oxidized
tocrine/paracrine mechanisms involving low-density lipoprotein receptor 1 medi-
TGF-β, PGE2, and PAF. J. Clin. Invest. ates phagocytosis of aged/apoptotic cells
101:890–98 in endothelial cells. Proc. Natl. Acad. Sci.
24. Pickering MC, Botto M, Taylor PR, Lach- USA 95:9535–40
mann PJ, Walport MJ. 2000. Systemic 34. Balasubramanian K, Schroit AJ. 1998.
lupus erythematosus, complement defi- Characterization of phosphatidylserine-
ciency, and apoptosis. Adv. Immunol. 76: dependent β2-glycoprotein I macrophage
227–324 interactions. Implications for apoptotic
25. Henson PM, Bratton DL, Fadok VA. cell clearance by phagocytes. J. Biol.
2001. Apoptotic cell removal. Curr. Biol. Chem. 273:29272–77
11:R795–805 35. Ogden CA, deCathelineau A, Hoffmann
26. Savill J, Dransfield I, Gregory C, Haslett PR, Bratton D, Ghebrehiwet B, et al. 2001.
C. 2002. A blast from the past: clearance C1q and mannose binding lectin engage-
of apoptotic cells regulates immune re- ment of cell surface calreticulin and CD91
sponses. Nat. Rev. Immunol. 2:965–75 initiates macropinocytosis and uptake of
27. Fadok VA, Voelker DR, Campbell PA, Co- apoptotic cells. J. Exp. Med. 194:781–95
hen JJ, Bratton DL, Henson PM. 1992. 36. Schagat TL, Wofford JA, Wright JR.
Exposure of phosphatidylserine on the 2001. Surfactant protein A enhances alve-
surface of apoptotic lymphocytes trig- olar macrophage phagocytosis of apop-
gers specific recognition and removal by totic neutrophils. J. Immunol. 166:2727–
macrophages. J. Immunol. 148:2207–16 33
28. Fadok VA, Bratton DL, Rose DM, Pear- 37. Vandivier RW, Ogden CA, Fadok VA,
son A, Ezekewitz RA, Henson PM. Hoffmann PR, Brown KK, et al. 2002.
938 TAYLOR ET AL.
Role of surfactant proteins A, D, and C1q ceptor mediate cell attachment through
in the clearance of apoptotic cells in vivo chondroitin sulphate glycosaminogly-
and in vitro: calreticulin and CD91 as a cans. Blood 102:2916–24
common collectin receptor complex. J. 47. Leemans JC, te Velde AA, Florquin S,
Immunol. 169:3978–86 Bennink RJ, de Bruin K, et al. 2004. The
38. Nakano T, Ishimoto Y, Kishino J, Umeda epidermal growth factor-seven transmem-
M, Inoue K, et al. 1997. Cell adhesion to brane (EGF-TM7) receptor CD97 is re-
phosphatidylserine mediated by a product quired for neutrophil migration and host
of growth arrest-specific gene 6. J. Biol. defense. J. Immunol. 172:1125–31
Chem. 272:29411–14 48. Hamann J, Wishaupt JO, van Lier RA,
39. Scott RS, McMahon EJ, Pop SM, Reap Smeets TJ, Breedveld FC, Tak PP. 1999.
EA, Caricchio R, et al. 2001. Phagocy- Expression of the activation antigen CD97
tosis and clearance of apoptotic cells is and its ligand CD55 in rheumatoid syn-
mediated by MER. Nature 411:207–11 ovial tissue. Arthritis Rheum. 42:650–58
40. Fan X, Krahling S, Smith D, Williamson 49. Visser L, de Vos AF, Hamann J, Melief
P, Schlegel RA. 2004. Macrophage Sur- MJ, van Meurs M, et al. 2002. Expression
face Expression of Annexins I and II in the of the EGF-TM7 receptor CD97 and its
Phagocytosis of Apoptotic Lymphocytes. ligand CD55 (DAF) in multiple sclerosis.
Mol. Biol. Cell 15:2863–72 J. Neuroimmunol. 132:156–63
41. Kwakkenbos MJ, Kop EN, Stacey M, 50. Stacey M, Lin HH, Hilyard KL, Gordon
Matmati M, Gordon S, et al. 2004. The S, McKnight AJ. 2001. Human epidermal
EGF-TM7 family: a postgenomic view. growth factor (EGF) module-containing
Immunogenetics 55:655–66 mucin-like hormone receptor 3 is a new
42. Schaller E, Macfarlane AJ, Rupec RA, member of the EGF-TM7 family that rec-
Gordon S, McKnight AJ, Pfeffer K. 2002. ognizes a ligand on human macrophages
Inactivation of the F4/80 glycoprotein in and activated neutrophils. J. Biol. Chem.
the mouse germ line. Mol. Cell. Biol. 22: 276:18863–70
8035–43 51. Hamann J, Kwakkenbos MJ, de Jong EC,
43. Warschkau H, Kiderlen AF. 1999. A Heus H, Olsen AS, van Lier RA. 2003.
monoclonal antibody directed against Inactivation of the EGF-TM7 receptor
the murine macrophage surface molecule EMR4 after the Pan-Homo divergence.
F4/80 modulates natural immune re- Eur. J. Immunol. 33:1365–71
sponse to Listeria monocytogenes. J. Im- 52. Wright SD, Ramos RA, Tobias PS, Ule-
munol. 163:3409–16 vitch RJ, Mathison JC. 1990. CD14, a
44. Wang Y, Goldschneider I, O’Rourke J, receptor for complexes of lipopolysaccha-
Cone RE. 2001. Blood mononuclear cells ride (LPS) and LPS binding protein. Sci-
induce regulatory NK T thymocytes in an- ence 249:1431–33
terior chamber-associated immune devia- 53. Lee JD, Kato K, Tobias PS, Kirkland TN,
tion. J. Leukoc. Biol. 69:741–46 Ulevitch RJ. 1992. Transfection of CD14
45. Lin H-H, Stacey M, Hamann J, Gordon into 70Z/3 cells dramatically enhances the
S, McKnight AJ. 2000. Human EMR2, sensitivity to complexes of lipopolysac-
a novel EGF-TM7 molecule on chromo- charide (LPS) and LPS binding protein.
some 19p13.1, is closely related to CD97. J. Exp. Med. 175:1697–705
Genomics 67:188–200 54. Van Amersfoort ES, Van Berkel TJ,
46. Stacey M, Chang GW, Davies JQ, Kuiper J. 2003. Receptors, mediators, and
Kwakkenbos MJ, Sanderson RD, et al. mechanisms involved in bacterial sepsis
2003. The epidermal growth factor- and septic shock. Clin. Microbiol. Rev.
like domains of the human EMR2 re- 16:379–414
55. Triantafilou M, Triantafilou K. 2002. uropathogenic and diarrhea-associated

Lipopolysaccharide recognition: CD14, Escherichia coli belong to a family of
TLRs and the LPS-activation cluster. hemagglutinins with Dr receptor recog-
Trends Immunol. 23:301–4 nition. Infect. Immun. 58:279–81
56. Ferrero E, Hsieh CL, Francke U, Goyert 65. Pham T, Kaul A, Hart A, Goluszko P,
SM. 1990. CD14 is a member of the fam- Moulds J, et al. 1995. dra-related X
ily of leucine-rich proteins and is encoded adhesins of gestational pyelonephritis-
by a gene syntenic with multiple receptor associated Escherichia coli recognize
genes. J. Immunol. 145:331–36 SCR-3 and SCR-4 domains of recombi-
57. Juan TS, Hailman E, Kelley MJ, Busse nant decay-accelerating factor. Infect. Im-
LA, Davy E, et al. 1995. Identification of mun. 63:1663–68
a lipopolysaccharide binding domain in 66. Nowicki B, Selvarangan R, Nowicki S.
CD14 between amino acids 57 and 64. J. 2001. Family of Escherichia coli Dr ad-
Biol. Chem. 270:5219–24 hesins: decay-accelerating factor recep-
58. Bazil V, Horejsi V, Baudys M, Kristofova tor recognition and invasiveness. J. Infect.
H, Strominger JL, et al. 1986. Biochem- Dis. 183(Suppl. 1):24–27
ical characterization of a soluble form 67. Le Bouguenec C, Lalioui L, du Merle L,
of the 53-kDa monocyte surface antigen. Jouve M, Courcoux P, et al. 2001. Charac-
Eur. J. Immunol. 16:1583–89 terization of AfaE adhesins produced by
59. Landmann R, Zimmerli W, Sansano S, extraintestinal and intestinal human Es-
Link S, Hahn A, et al. 1995. Increased cherichia coli isolates: PCR assays for
circulating soluble CD14 is associated detection of Afa adhesins that do or do
with high mortality in gram-negative sep- not recognize Dr blood group antigens. J.
tic shock. J. Infect Dis. 171:639–44 Clin. Microbiol. 39:1738–45
60. Lublin DM, Atkinson JP. 1989. Decay- 68. Caras IW, Davitz MA, Rhee L, Weddell
accelerating factor: biochemistry, molec- G, Martin DW Jr, Nussenzweig V. 1987.
ular biology, and function. Annu. Rev. Cloning of decay-accelerating factor sug-
Immunol. 7:35–58 gests novel use of splicing to generate two
61. Lindahl G, Sjobring U, Johnsson E. 2000. proteins. Nature 325:545–49
Human complement regulators: a ma- 69. Lea S. 2002. Interactions of CD55 with
jor target for pathogenic microorganisms. non-complement ligands. Biochem. Soc.
Curr. Opin. Immunol. 12:44–51 Trans. 30:1014–19
62. Ward T, Pipkin PA, Clarkson NA, Stone 70. Hamann J, Vogel B, van Schijndel GM,
DM, Minor PD, Almond JW. 1994. van Lier RA. 1996. The seven-span trans-
Decay-accelerating factor CD55 is identi- membrane receptor CD97 has a cellular
fied as the receptor for echovirus 7 using ligand (CD55, DAF). J. Exp. Med. 184:
CELICS, a rapid immuno-focal cloning 1185–89
method. EMBO J. 13:5070–74 71. Lin HH, Stacey M, Saxby C, Knott V,
63. Bergelson JM, Mohanty JG, Crowell Chaudhry Y, et al. 2001. Molecular anal-
RL, St. John NF, Lublin DM, Finberg ysis of the epidermal growth factor-like
RW. 1995. Coxsackievirus B3 adapted short consensus repeat domain-mediated
to growth in RD cells binds to decay- protein-protein interactions: dissection of
accelerating factor (CD55). J. Virol. 69: the CD97-CD55 complex. J. Biol. Chem.
1903–6 276:24160–69
64. Nowicki B, Labigne A, Moseley S, Hull 72. Lawrence DW, Bruyninckx WJ, Louis
R, Hull S, Moulds J. 1990. The Dr NA, Lublin DM, Stahl GL, et al. 2003.
hemagglutinin, afimbrial adhesins AFA-I Antiadhesive role of apical decay-
and AFA-III, and F1845 fimbriae of accelerating factor (CD55) in human
940 TAYLOR ET AL.
neutrophil transmigration across mucosal acids and innate immunity. Trends Im-
epithelia. J. Exp. Med. 198:999–1010 munol. 22:337–42
73. Colonna M. 2003. TREMs in the immune 83. Brinkman-Vander Linden ECM, Angata
system and beyond. Nat. Rev. Immunol. 3: T, Reynolds SA, Powell LD, Hedrick SM,
445–53 Varki A. 2003. CD33/Siglec-3 binding
74. Colonna M, Facchetti F. 2003. TREM-1 specificity, expression pattern, and con-
(triggering receptor expressed on myeloid sequences of gene deletion in mice. Mol.
cells): a new player in acute inflammatory Cell. Biol. 23:4199–206
responses. J. Infect. Dis. 187(Suppl. 2): 84. Colonna M, Nakajima H, Cella M. 2000.
S397–401 A family of inhibitory and activating Ig-
75. Bleharski JR, Kiessler V, Buonsanti C, like receptors that modulate function of
Sieling PA, Stenger S, et al. 2003. A lymphoid and myeloid cells. Semin. Im-
role for triggering receptor expressed on munol. 12:121–27
myeloid cells-1 in host defense during the 85. Ho LH, Uehara T, Chen CC, Kubagawa H,
early-induced and adaptive phases of the Cooper MD. 1999. Constitutive tyrosine
immune response. J. Immunol. 170:3812– phosphorylation of the inhibitory paired
18 Ig-like receptor PIR-B. Proc. Natl. Acad.
76. Bouchon A, Facchetti F, Weigand MA, Sci. USA 96:15086–90
Colonna M. 2001. TREM-1 amplifies in- 86. Ujike A, Takeda K, Nakamura A, Ebihara
flammation and is a crucial mediator of S, Akiyama K, Takai T. 2002. Impaired
septic shock. Nature 410:1103–7 dendritic cell maturation and increased
77. Kaifu T, Nakahara J, Inui M, Mishima K, T(H)2 responses in PIR-B−/− mice. Nat.
Momiyama T, et al. 2003. Osteopetrosis Immunol. 3:542–48
and thalamic hypomyelinosis with synap- 87. Nakamura A, Kobayashi E, Takai T. 2004.
tic degeneration in DAP12-deficient mice. Exacerbated graft-versus-host disease in
J. Clin. Invest. 111:323–32 Pirb−/− mice. Nat. Immunol. 5:623–29
78. Crocker PR. 2002. Siglecs: sialic-acid- 88. Barclay AN, Wright GJ, Brooke G, Brown
binding immunoglobulin-like lectins in MH. 2002. CD200 and membrane pro-
cell-cell interactions and signalling. Curr. tein interactions in the control of myeloid
Opin. Struct. Biol. 12:609–15 cells. Trends Immunol. 23:285–90
79. Crocker PR, Gordon S. 1986. Properties 89. Hoek RM, Ruuls SR, Murphy CA, Wright
and distribution of a lectin-like hemagglu- GJ, Goddard R, et al. 2000. Down-
tinin differentially expressed by murine regulation of the macrophage lineage
stromal tissue macrophages. J. Exp. Med. through interaction with OX2 (CD200).
164:1862–75 Science 290:1768–71
80. Jones C, Virji M, Crocker PR. 2003. 90. Kharitonenkov A, Chen ZJ, Sures I, Wang
Recognition of sialylated meningococcal HY, Schilling J, Ullrich A. 1997. A
lipopolysaccharide by siglecs expressed family of proteins that inhibit signalling
on myeloid cells leads to enhanced bac- through tyrosine kinase receptors. Nature
terial uptake. Mol. Microbiol. 49:1213– 386:181–86
25 91. Oldenborg PA, Gresham HD, Lindberg
81. Paul SP, Taylor LS, Stansbury EK, FP. 2001. CD47-signal regulatory protein
McVicar DW. 2000. Myeloid specific α (SIRP α) regulates Fc γ and comple-
human CD33 is an inhibitory receptor ment receptor-mediated phagocytosis. J.
with differential ITIM function in recruit- Exp. Med. 193:855–62
ing the phosphatases SHP-1 and SHP-2. 92. Brown EJ, Frazier WA. 2001. Integrin-
Blood 96:483–90 associated protein (CD47) and its ligands.
82. Crocker PR, Varki A. 2001. Siglecs, sialic Trends Cell Biol. 11:130–35
93. Oldenborg PA, Zheleznyak A, Fang YF, immunoreceptor and its ligands. Nat. Rev.
Lagenaur CF, Gresham HD, Lindberg FP. Immunol. 3:781–90
2000. Role of CD47 as a marker of self 101. Diefenbach A, Tomasello E, Lucas M,
on red blood cells. Science 288:2051– Jamieson AM, Hsia JK, et al. 2002. Selec-
54 tive associations with signaling proteins
94. Gardai SJ, Xiao YQ, Dickinson M, Nick determine stimulatory versus costimula-
JA, Voelker DR, et al. 2003. By binding tory activity of NKG2D. Nat. Immunol.
SIRP α or calreticulin/CD91, lung col- 3:1142–49
lectins act as dual function surveillance 102. Herre J, Gordon S, Brown GD. 2004.
molecules to suppress or enhance inflam- Dectin-1 and its role in the recognition of
mation. Cell 115:13–23 beta-glucans by macrophages. Mol. Im-
95. Toyama-Sorimachi N, Tsujimura Y, munol. 40:869–76
Maruya M, Onoda A, Kubota T, et al. 103. Mantegazza AR, Barrio MM, Moutel
2004. Ly49Q, a member of the Ly49 S, Bover L, Weck M, et al. 2004.
family that is selectively expressed on CD63 Tetraspanin slows down cell
myeloid lineage cells and involved in reg- migration and translocates to the endo-
ulation of cytoskeletal architecture. Proc. somal/lysosomal/MIICs route after extra-
Natl. Acad. Sci. USA 101:1016–21 cellular stimuli in human immature den-
96. Roda-Navarro P, Arce I, Renedo M, dritic cells. Blood 104:1183–90
Montgomery K, Kucherlapati R, Fer- 104. Willment JA, Lin HH, Reid DM, Tay-
nandez-Ruiz E. 2000. Human KLRF1, a lor PR, Williams DL, et al. 2003.
novel member of the killer cell lectin- Dectin-1 expression and function are en-
like receptor gene family: molecular char- hanced on alternatively activated and
acterization, genomic structure, physical GM-CSF-treated macrophages and are
mapping to the NK gene complex and negatively regulated by IL-10, dexam-
expression analysis. Eur. J. Immunol. ethasone, and lipopolysaccharide. J. Im-
30:568–76 munol. 171:4569–73
97. Marshall AS, Willment JA, Lin HH, 105. Steele C, Marrero L, Swain S, Harm-
Williams DL, Gordon S, Brown GD. sen AG, Zheng M, et al. 2003. Alveolar
2004. Identification and characterization macrophage-mediated killing of Pneumo-
of a novel human myeloid inhibitory cystis carinii f. sp. muris involves molec-
C-type lectin-like receptor (MICL) that ular recognition by the Dectin-1 beta-
is predominantly expressed on granu- glucan receptor. J. Exp. Med. 198:1677–
locytes and monocytes. J. Biol. Chem. 88
279:14792–802 106. Gantner BN, Simmons RM, Canavera SJ,
98. Colonna M, Samaridis J, Angman L. Akira S, Underhill DM. 2003. Collabora-
2000. Molecular characterization of two tive induction of inflammatory responses
novel C-type lectin-like receptors, one of by dectin-1 and Toll-like receptor 2. J.
which is selectively expressed in human Exp. Med. 197:1107–17
dendritic cells. Eur. J. Immunol. 30:697– 107. Brown GD, Herre J, Williams DL, Will-
704 ment JA, Marshall AS, Gordon S. 2003.
99. Bakker AB, Baker E, Sutherland GR, Dectin-1 mediates the biological effects of
Phillips JH, Lanier LL. 1999. Myeloid beta-glucans. J. Exp. Med. 197:1119–24
DAP12-associating lectin (MDL)-1 is a 108. Herre J, Marshall AS, Caron E, Edwards
cell surface receptor involved in the acti- AD, Williams DL, et al. 2004. Dectin-1
vation of myeloid cells. Proc. Natl. Acad. utilises novel mechanisms for yeast
Sci. USA 96:9792–96 phagocytosis in macrophages. Blood. In
100. Raulet DH. 2003. Roles of the NKG2D press
942 TAYLOR ET AL.
109. Reid DM, Montoya M, Taylor PR, Bor- transmitting receptors. J. Exp. Med. 178:
row P, Gordon S, et al. 2004. Expression 537–47
of the beta-glucan receptor, Dectin-1, on 117. Pavlicek J, Sopko B, Ettrich R, Kopecky
murine leukocytes in situ correlates with V Jr, Baumruk V, et al. 2003. Molecular
its function in pathogen recognition and characterization of binding of calcium and
reveals potential roles in leukocyte inter- carbohydrates by an early activation anti-
actions. J. Leukoc. Biol. 76:86–94 gen of lymphocytes CD69. Biochemistry
110. Chen M, Masaki T, Sawamura T. 2002. 42:9295–306
LOX-1, the receptor for oxidized low- 118. Marzio R, Jirillo E, Ransijn A, Mauel J,
density lipoprotein identified from en- Corradin SB. 1997. Expression and func-
dothelial cells: implications in endothelial tion of the early activation antigen CD69
dysfunction and atherosclerosis. Pharma- in murine macrophages. J. Leukoc. Biol.
col. Ther. 95:89–100 62:349–55
111. Xie Q, Matsunaga S, Niimi S, Ogawa 119. Pisegna S, Zingoni A, Pirozzi G, Cinque
S, Tokuyasu K, et al. 2004. Human B, Cifone MG, et al. 2002. Src-dependent
lectin-like oxidized low-density lipopro- Syk activation controls CD69-mediated
tein receptor-1 functions as a dimer in signaling and function on human NK
living cells. DNA Cell Biol. 23:111– cells. J. Immunol. 169:68–74
17 120. Lauzurica P, Sancho D, Torres M, Al-
112. Delneste Y, Magistrelli G, Gauchat J, bella B, Marazuela M, et al. 2000. Phe-
Haeuw J, Aubry J, et al. 2002. In- notypic and functional characteristics of
volvement of LOX-1 in dendritic cell- hematopoietic cell lineages in CD69-
mediated antigen cross-presentation. Im- deficient mice. Blood 95:2312–20
munity 17:353–62 121. Esplugues E, Sancho D, Vega-Ramos J,
113. Honjo M, Nakamura K, Yamashiro K, Martinez C, Syrbe U, et al. 2003. En-
Kiryu J, Tanihara H, et al. 2003. Lectin- hanced antitumor immunity in mice de-
like oxidized LDL receptor-1 is a cell- ficient in CD69. J. Exp. Med. 197:1093–
adhesion molecule involved in endotoxin- 106
induced inflammation. Proc. Natl. Acad. 122. Sancho D, Gomez M, Viedma F, Es-
Sci. USA 100:1274–79 plugues E, Gordon-Alonso M, et al. 2003.
114. Cebrian M, Yague E, Rincon M, Lopez- CD69 downregulates autoimmune reac-
Botet M, de Landazuri MO, Sanchez- tivity through active transforming growth
Madrid F. 1988. Triggering of T cell factor-β production in collagen-induced
proliferation through AIM, an activa- arthritis. J. Clin. Invest. 112:872–82
tion inducer molecule expressed on acti- 123. Plougastel B, Dubbelde C, Yokoyama
vated human lymphocytes. J. Exp. Med. WM. 2001. Cloning of Clr, a new fam-
168:1621–37 ily of lectin-like genes localized between
115. Marzio R, Mauel J, Betz-Corradin S. mouse Nkrp1a and Cd69. Immunogenet-
1999. CD69 and regulation of the im- ics 53:209–14
mune function. Immunopharmacol. Im- 124. Carlyle JR, Jamieson AM, Gasser S, Clin-
munotoxicol. 21:565–82 gan CS, Arase H, Raulet DH. 2004.
116. Lopez-Cabrera M, Santis AG, Fernandez- Missing self-recognition of Ocil/Clr-b by
Ruiz E, Blacher R, Esch F, et al. inhibitory NKR-P1 natural killer cell re-
1993. Molecular cloning, expression, and ceptors. Proc. Natl. Acad. Sci. USA 101:
chromosomal localization of the human 3527–32
earliest lymphocyte activation antigen 125. Iizuka K, Naidenko OV, Plougastel BF,
AIM/CD69, a new member of the C- Fremont DH, Yokoyama WM. 2003.
type animal lectin superfamily of signal- Genetically linked C-type lectin-related
ligands for the NKRP1 family of natural specific HIV-1-binding protein that en-
killer cell receptors. Nat. Immunol. 4:801– hances trans-infection of T cells. Cell 100:
7 587–97
126. Zhou H, Kartsogiannis V, Quinn JM, 135. Geijtenbeek TB, Torensma R, van Vliet
Ly C, Gange C, Elliott J, et al. 2002. SJ, van Duijnhoven GC, Adema GJ, et al.
Osteoclast inhibitory lectin, a family of 2000. Identification of DC-SIGN, a novel
new osteoclast inhibitors. J. Biol. Chem. dendritic cell-specific ICAM-3 receptor
277:48808–15 that supports primary immune responses.
127. Gange CT, Quinn JM, Zhou H, Kartso- Cell 100:575–85
giannis V, Gillespie MT, Ng KW. 2004. 136. Geijtenbeek TB, Groot PC, Nolte MA,
Characterization of sugar binding by os- van Vliet SJ, Gangaram-Panday ST,
teoclast inhibitory lectin. J. Biol. Chem. et al. 2002. Marginal zone macrophages
279:29043–49 express a murine homologue of DC-
128. Kanazawa N, Tashiro K, Inaba K, Miy- SIGN that captures blood-borne antigens
achi Y. 2003. Dendritic cell immunoac- in vivo. Blood 100:2908–16
tivating receptor, a novel C-type lectin 137. Kang YS, Yamazaki S, Iyoda T, Pack M,
immunoreceptor, acts as an activating re- Bruening SA, et al. 2003. SIGN-R1, a
ceptor through association with Fc recep- novel C-type lectin expressed by marginal
tor γ chain. J. Biol. Chem. 278:32645–52 zone macrophages in spleen, mediates up-
129. Bates EE, Fournier N, Garcia E, Val- take of the polysaccharide dextran. Int.
ladeau J, Durand I, et al. 1999. APCs Immunol. 15:177–86
express DCIR, a novel C-type lectin sur- 138. Geijtenbeek TB, Krooshoop DJ, Bleijs
face receptor containing an immunore- DA, van Vliet SJ, van Duijnhoven GC,
ceptor tyrosine-based inhibitory motif. J. et al. 2000. DC-SIGN-ICAM-2 interac-
Immunol. 163:1973–83 tion mediates dendritic cell trafficking.
130. Balch SG, McKnight AJ, Seldin MF, Gor- Nat. Immunol. 1:353–57
don S. 1998. Cloning of a novel C-type 139. Park CG, Takahara K, Umemoto E,
lectin expressed by murine macrophages. Yashima Y, Matsubara K, et al. 2001. Five
J. Biol. Chem. 273:18656–64 mouse homologues of the human den-
131. Mizuochi S, Akimoto Y, Imai Y, Hirano dritic cell C-type lectin, DC-SIGN. Int.
H, Irimura T. 1997. Unique tissue dis- Immunol. 13:1283–90
tribution of a mouse macrophage C-type 140. Kang YS, Kim JY, Bruening SA, Pack
lectin. Glycobiology 7:137–46 M, Charalambous A, et al. 2004. The C-
132. Tsuiji M, Fujimori M, Ohashi Y, Hi- type lectin SIGN-R1 mediates uptake of
gashi N, Onami TM, et al. 2002. Molec- the capsular polysaccharide of Strepto-
ular cloning and characterization of a coccus pneumoniae in the marginal zone
novel mouse macrophage C-type lectin, of mouse spleen. Proc. Natl. Acad. Sci.
mMGL2, which has a distinct carbohy- USA 101:215–20
drate specificity from mMGL1. J. Biol. 141. Fernandes MJ, Finnegan AA, Siracusa
Chem. 277:28892–901 LD, Brenner C, Iscove NN, Calabretta B.
133. Matsumoto M, Tanaka T, Kaisho T, Sanjo 1999. Characterization of a novel recep-
H, Copeland NG, et al. 1999. A novel tor that maps near the natural killer gene
LPS-inducible C-type lectin is a transcrip- complex: demonstration of carbohydrate
tional target of NF-IL6 in macrophages. J. binding and expression in hematopoietic
Immunol. 163:5039–48 cells. Cancer Res. 59:2709–17
134. Geijtenbeek TB, Kwon DS, Torensma 142. Ariizumi K, Shen GL, Shikano S, Ritter R
R, van Vliet SJ, van Duijnhoven GC, 3rd, Zukas P, et al. 2000. Cloning of a sec-
et al. 2000. DC-SIGN, a dendritic cell- ond dendritic cell-associated C-type lectin
944 TAYLOR ET AL.
(dectin-2) and its alternatively spliced iso- of the mannose receptor. Immunobiology
forms. J. Biol. Chem. 275:11957–63 204:527–35
143. Aragane Y, Maeda A, Schwarz A, Tezuka 149. Roseman DS, Baenziger JU. 2000.
T, Ariizumi K, Schwarz T. 2003. Involve- Molecular basis of lutropin recognition
ment of dectin-2 in ultraviolet radiation- by the mannose/GalNAc-4-SO4 receptor.
induced tolerance. J. Immunol. 171:3801– Proc. Natl. Acad. Sci. USA 97:9949–54
7 150. Sheikh H, Yarwood H, Ashworth A,
144. Pontow SE, Kery V, Stahl PD. 1992. Man- Isacke CM. 2000. Endo180, an endo-
nose receptor. Int. Rev. Cytol. 137B:221– cytic recycling glycoprotein related to
44 the macrophage mannose receptor is ex-
145. East L, Isacke CM. 2002. The mannose pressed on fibroblasts, endothelial cells
receptor family. Biochim. Biophys. Acta and macrophages and functions as a lectin
1572:364–86 receptor. J. Cell Sci. 113:1021–32
146. Lee SJ, Evers S, Roeder D, Parlow AF, 151. Engelholm LH, Nielsen BS, Dano K,
Risteli J, et al. 2002. Mannose receptor- Behrendt N. 2001. The urokinase receptor
mediated regulation of serum glycopro- associated protein (uPARAP/endo180): a
tein homeostasis. Science 295:1898–901 novel internalization receptor connected
147. Taylor ME, Drickamer K. 1993. Struc- to the plasminogen activation system.
tural requirements for high affinity bind- Trends Cardiovasc. Med. 11:7–13
ing of complex ligands by the macrophage 152. East L, McCarthy A, Wienke D, Sturge
mannose receptor. J. Biol. Chem. 268: J, Ashworth A, Isacke CM. 2003. A tar-
399–404 geted deletion in the endocytic receptor
148. Martinez-Pomares L, Linehan SA, Taylor gene Endo180 results in a defect in colla-
PR, Gordon S. 2001. Binding properties gen uptake. EMBO Rep. 4:710–16
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Macrophage Receptors and Immune Recognition: Annual Review of Immunology February 2005

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Macrophage Receptors and Immune Recognition: Annual Review of Immunology February 2005

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Macrophage receptors and immune recognition

Article in Annual Review of Immunology · February 2005

Luisa Martinez-Pomares Martin Stacey

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MACROPHAGE RECEPTORS AND IMMUNE

Key Words pattern recognition, innate immunity, phagocytosis, micro-organisms,

902 TAYLOR ET AL.

TABLE 1 Overview of MØ receptors implicated in immune recognitiona

Scavenger (collagenous) SR-A Phagocytosis of bacteria and

detailed discussion of receptors for cytokines, chemokines, selectins, and inte-

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 903

PATTERN RECOGNITION, AN EVOLVING CONCEPT

904 TAYLOR ET AL.

during their differentiation, migration into different tissue microenvironments,

HETEROGENEOUS ANTIGEN AND SURFACE

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 905

Figure 1 Phenotypic heterogeneity of monocytes/MØ and DCs during differentiation

Dectin-1. In such a relatively opsonin-poor environment, the expression of spe-

MØ HETEROGENEITY AND THE SPLEEN

906 TAYLOR ET AL.

TABLE 2 Macrophage activation: heterogeneity of phenotypea

Effects on ↑ MARCO ↑ MHC class II ↑ MR

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION

MØ. Schematic diagram based on G. Kraal (12).

908 TAYLOR ET AL.

express an array of PRR including the scavenger receptor-A (SR-A), macrophage

SCAVENGER RECEPTORS AND MICROBIAL

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 909

910 TAYLOR ET AL.

TABLE 3 Phenotypes derived from receptor/ligand knockouts

Scavenger and related

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 911

Non-phagocytic ligands have also been reported on B lymphocytes, which may

RECOGNITION OF APOPTOTIC CELLS BY MØ

912 TAYLOR ET AL.

MØ and the identification of multiple candidate receptors (25, 26). Although to

Vitronectin Receptor (αvβ3-integrin)

Phosphatidyl Serine Receptor (PSR)

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 913

CD14 Characterization of a mAb that blocked the recognition of apoptotic cells

Complement Receptors 3 and 4 (CR3 and CR4)

CD91-Calreticulin Recognition of C1q, SP-A, and SP-D

914 TAYLOR ET AL.

cell recognition, investigations in mice led to the discovery of a differential im-

MER and Gas6

SEVEN TRANSMEMBRANE RECEPTORS

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 915

The EGF-M7 Family

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 917

anterior chamber-associated immune deviation have demonstrated a role for F4/80

918 TAYLOR ET AL.

characterized by the dense infiltration of MØ and lymphocytes. Recent sequencing

EMR4 Mouse EMR4 is predominantly expressed on resident MØ. The expres-

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 919

MEMBERS OF THE IMMUNOGLOBULIN

920 TAYLOR ET AL.

Triggering Receptors Expressed by Myeloid Cells (TREMs)

TREM1 TREM1 is expressed by monocytes/MØ and neutrophils and associates

MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION 921

inflammatory protein 1α (MIP1α) (75). Anti-TREM1 mAb also enhances LPS-