Download The function of Fcγ receptors in dendritic cells and macrophages

REVIEWS
The function of Fcγ receptors in
dendritic cells and macrophages
Martin Guilliams1,2, Pierre Bruhns3,4, Yvan Saeys1,2, Hamida Hammad1,2 and
Bart N. Lambrecht1,2,5
Abstract | Dendritic cells (DCs) and macrophages use various receptors to recognize foreign
antigens and to receive feedback control from adaptive immune cells. Although it was long
believed that all immunoglobulin Fc receptors are universally expressed by phagocytes,
recent findings indicate that only monocyte-derived DCs and macrophages express high
levels of activating Fc receptors for IgG (FcγRs), whereas conventional and plasmacytoid DCs
express the inhibitory FcγR. In this Review, we discuss how the uptake, processing and
presentation of antigens by DCs and macrophages is influenced by FcγR recognition of
immunoglobulins and immune complexes in the steady state and during inflammation.
Laboratory of
Immunoregulation, VIB
Inflammation Research
Center, 9052 Ghent, Belgium.
2
Department of Respiratory
Medicine, Ghent University,
9000 Ghent, Belgium.
3
Institut Pasteur,
Département d’Immunologie,
Laboratoire Anticorps en
Thérapie et Pathologie,
75015 Paris, France.
4
Institut National de la Santé
et de la Recherche Médicale,
U760, 75015 Paris, France.
5
Department of Pulmonary
Medicine, Erasmus University
Medical Center, 3015
Rotterdam, The Netherlands.
Correspondence to M.G. and
B.N.L.
e-mails: martin.guilliams@
irc.vib-ugent.be;
bart.lambrecht@
irc.vib-ugent.be
doi:10.1038/nri3582
Published online
21 January 2014
Corrected online 7 April 2014
1
Dendritic cells (DCs) and macrophages bridge innate
and adaptive immunity by recognizing and internalizing foreign antigens and by subsequently processing
the antigens for presentation to cells of the adaptive
immune system. Once the adaptive immune response
has been initiated, innate immune cells receive important feedback signals from adaptive immune cells; for
example, T cell-derived cytokines increase the innate
effector functions of macrophages and neutrophils.
Importantly, B cell-derived immunoglobulins that
develop a few days after antigen encounter also regulate the function of innate immune cells, as most innate
immune cells express various Fc receptors (FcRs) for
IgG (FcγRs), IgM, IgA and IgE. The killing of infected
cells by neutrophils and natural killer (NK) cells is facilitated by opsonization by IgGs — a process that is known
as antibody-dependent cell-mediated cytotoxicity (ADCC).
Similarly, the degranulation of mast cells and basophils
is induced by crosslinking of IgE that is bound to the
high-affinity FcR for IgE (FcεRI)1,2.
In this Review we address the feedback control of
DC and macrophage function by immunoglobulins
and by antigen–antibody complexes, which are known
as immune complexes, focusing mainly on the functions
of FcγRs. Targeting antigens to phagocytes via FcRs
markedly affects antigen uptake, endosomal maturation, antigen processing and cellular activation. Most
papers that address the function of FcRs on phagocytes have conceptually grouped DCs, macrophages
and monocytes together as cells of the common mononuclear phagocyte system (MPS), which has led to the
dogma that all FcRs are expressed by all cells of the
MPS. The concept of the MPS has undergone considerable changes in the past 10 years, and now different
subsets of DCs and macrophages that differ in their
FcR expression can be clearly delineated (BOX 1). Given
these recent developments, we summarize in this
Review what is currently known about FcγR triggering on DC and macrophage subsets in the steady state
and in inflammatory disease states, and we identify
areas for future research.
A primer on FcγRs
Myeloid cells express various FcγRs that facilitate
their interaction with monomeric or aggregated
IgGs, immune complexes and opsonized (antibodycoated) particles or cells (TABLES 1,2). Most receptors
bind extracellular IgGs, with the exception of the
neonatal FcR (FcRn)3 and the intracellular FcR tripartite motif-containing protein 21 (TRIM21)4,5, which
bind to immunoglobulins following their internalization. The various FcγRs are functionally divided into
activating and inhibitory receptors. Activating FcγRs
have an immunoreceptor tyrosine-based activation
motif (ITAM) in their intracytoplasmic domain or, in
the case of the high-affinity FcR for IgG (FcγRI; also
known as CD64) and FcγRIIIA, associate with the
ITAM-containing signalling subunit FcR common
γ‑chain (encoded by FCER1G) (TABLES 1,2). Following
receptor activation by immune complexes, the ITAMs
activate signalling cascades via SRC family kinases and
spleen tyrosine kinase (SYK)2,6,7. The inhibitory FcγR,
FcγRIIB, has an immunoreceptor tyrosine-based inhibition motif (ITIM) in its intracytoplasmic domain8.
94 | FEBRUARY 2014 | VOLUME 14
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 1 | Use of FcRs to distinguish moDCs and macrophages from cDCs
The high-affinity Fc receptor I for IgG (FcγRI; also known as CD64) and the high-affinity
Fc receptor for IgE (FcεRI) have recently been suggested to be the best markers to
separate monocyte-derived cells (that is, macrophages and monocyte-derived
dendritic cells (moDCs)) from conventional DCs (cDCs). The idea that Fc receptor (FcR)
expression can be used to distinguish between myeloid cell subpopulations is not
new. In fact, in one of the two original papers152 in which Nobel prize laureate Ralph
Steinman described the discovery of splenic DCs, he noticed that splenic DCs are
very different from macrophages in that they poorly bind immune complexes and
antibody-coated sheep red blood cells. The Malissen team36,37 and the Randolph team25
have recently independently found that an antibody against FcγRI could be used to
discriminate moDCs and macrophages from cDCs.
The Malissen team36,37 tested antibodies that are specific for known monocyteand/or macrophage-specific markers (that is, F4/80, CD115 (which is the macrophage
colony-stimulating factor (M‑CSF) receptor), CD68, CX3C-chemokine receptor 1
(CX3CR1), LY6C, CD43 and FcγRI) and DC‑specific markers (that is, CD11c, 33D1 and
high expression levels of MHC class II molecules) in mixed bone-marrow chimeric mice
that had been reconstituted with 50% bone marrow from wild-type mice and 50% bone
marrow from CC‑chemokine receptor 2 (Ccr2)–/– mice. Bone marrow from Ccr2−/− mice
was used because monocytes require CCR2 for their egress from the bone marrow142.
As a result, in these mixed chimeric mice monocyte-derived cells can be identified
because these cells will almost all be derived from the bone marrow from wild-type
mice and not from the bone marrow from Ccr2−/− mice, whereas all the other
non-monocytic cells will have a mixed chimerism because they will be derived from
both the wild-type and the Ccr2−/− bone marrow. They found that only FcγRI expression
facilitated the correct separation of moDCs and macrophages from cDCs36,37.
The Randolph laboratory25, through their participation in the Immunological Genome
Consortium (see Further information), found that the expression of FcγRI was one of the
best markers to discriminate macrophages from cDCs, together with the expression of
the tyrosine protein kinase MER (MERTK). In addition, the Lambrecht laboratory23,144
found that FcεRI is highly expressed by moDCs and combining an FcγRI-specific
antibody (clone X54–5/7.1) and an FcεRI-specific antibody (clone MAR‑1) is the most
specific and sensitive way to distinguish moDCs from cDCs compared with other
commonly used discriminating markers. Interestingly, the Amigorena laboratory43 found
that human inflammatory moDCs but not macrophages express high levels of FcεRI,
which identifies FcεRI as a good moDC marker in mice and humans.
Antibody-dependent
cell-mediated cytotoxicity
(ADCC). A mechanism by
which cytotoxic effector cells,
including natural killer (NK)
cells, kill other cells, for
example, virus-infected target
cells that are coated with
antibodies. The Fc portions of
the coating antibodies interact
with the Fc receptor that is
expressed by the cytotoxic
effector cell, thereby initiating
a signalling cascade that leads
to cellular activation and target
cell killing. The precise killing
mechanism depends on the
type of cytotoxic effector cell.
This ITIM recruits SH2 domain-containing inositol
5ʹ‑phosphatase 1 (SHIP1; encoded by INPP5D)9 and
thus counteracts the signals that are mediated by
activating FcγRs10,11.
Another classification of FcγRs is based on the
affinity of the receptor for IgG: FcγRs with different
affinities for different IgG isotypes can bind to multiple
classes of immunoglobulin12 (TABLES 1,2). A few receptors — such as FcγRI, FcγRIV and FcRn — can bind
to monomeric IgG (which is the definition of highaffinity receptors), whereas the other receptors mainly
bind to aggregated IgGs. Although for some researchers the definition of FcγRIV as a high-affinity receptor
is debatable2,13, we think that the main factor for consideration when dividing FcγRs into high-affinity or
low-affinity receptors should be their capacity to bind
monomeric IgGs; on the basis of this criterion, we consider FcγRIV to be a high-affinity receptor 14,15. It was
initially thought that the high-affinity FcγRs were unavailable for immediate immunoglobulin-dependent
responses in vivo because they were occupied or saturated by endogenous immunoglobulins; however, this
viewpoint is no longer supported14–17. Adding to the
complexity of FcγR nomenclature and biology, polymorphisms have been described in FcγRs of mice and
humans; for example, polymorphisms in FCGR2A (the
gene encoding FcγRIIA) and FCGR3A (the gene encoding FcγRIIIA) modulate the affinity of the receptors they
encode for some human IgG subclasses12, and some of
these polymorphisms have been linked to disease18. The
binding characteristics of IgG subclasses to particular
FcγRs can be modified by altering critical amino acid
residues, or their glycosylation status, in the amino acid
backbone of the Fc fragment of the antibody, in or near
the site of interaction with the FcγR. In particular, the
nature and the presence of N‑linked glycan structures at
residue Asn297 in IgG can modulate or even abrogate
FcγR binding, which thus affects the immune response
that is induced. These modifications are now being
exploited to alter the effector functions of therapeutic antibodies that are used in cancer treatment and autoimmune
disease (reviewed in REF. 19).
Expression of FcγRs by DCs and macrophages
There is a consensus that different subsets of DCs carry
out different functions20 (BOX 2). There are two main
developmentally distinct subsets of conventional DCs
(cDCs): CD172α (also known as SIRPα)+ cDCs are
functionally specialized to present exogenous antigens
to CD4+ T cells and to help humoral immunity 21–23,
whereas XC-chemokine receptor 1 (XCR1)+ cDCs are
specialized for the cross-presentation of exogenous antigens to CD8+ T cells. Plasmacytoid DCs (pDCs) provide
an important and early source of type I interferon (IFN)
during viral infections. Monocytes are separated in classical monocytes (LY6Chi in mice and CD14hi in humans)
and patrolling monocytes (CX3C-chemokine receptor 1 (CX3CR1)hiLY6Clow in mice and CD14lowCD16hi in
humans). In tissues, classical monocytes can give rise to
monocyte-derived DCs (moDCs), the function of which is
to control local effector CD4+ and CD8+ T cell responses.
Macrophages have been separated into tissue-resident
macrophages (such as microglial cells in the brain,
Kupffer cells in the liver and alveolar macrophages in
the lungs) and recruited macrophages. Recruited macro­
phages and moDCs are absent from most tissues in the
steady state but rapidly accumulate from newly recruited
monocytes following the induction of inflammation.
As in vitro-generated moDCs have long been considered to represent in vivo DCs, and as their maturation could be enhanced through the stimulation of
activating FcγRs and suppressed through the inhibitory FcγR, it was thought that all FcγRs were broadly
expressed by all DC subsets2,11,24. However, by compiling publicly available gene expression data (from
the Immunological Genome Consortium 25,26 and
from published research articles) from freshly isolated DC and macrophage subsets, it is evident that
the expression of FcγRs is highly selective (FIG. 1; see
Supplementary information S1 (figure)). Activating
FcγR mRNAs (Fcgr1, Fcgr3 and Fcgr4 in mice and
FCGR1, FCGR2A, FCGR2C and FCGR3A in humans)
are predominantly found in monocytes, macrophages
and moDCs. Inhibitory Fcgr2b mRNA is broadly
expressed by mouse cDCs and pDCs, as well as by
moDCs and macrophages. Human cDCs and pDCs
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | FEBRUARY 2014 | 95
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Table 1 | Human Fc receptors for IgG
Structure
Name
CD
Gene
Alleles* IgG1
IgG2
IgG3
IgG4
Major function
FcγRI
CD64
FCGR1A
–
6x10
No
binding
6x10
3x10
Activation
FcγRIIA
CD32A
FCGR2A
His131
Arg131
5x106
3x106
4x105
1x105
9x105
9x105
2x105
2x105
Activation
FcγRIIB
CD32B
FCGR2B
Ile232
Thr232
1x105
1x105
2x104
2x104
2x105
2x105
2x105
2x105
Inhibition
FcγRIIC
CD32C
FCGR2C
Gln13
Stop13
1x105
2x104
2x105
2x105
Activation
FcγRIIIA
CD16A
FCGR3A
Val158
Phe158
2x105
1x105
7x104
3x104
10x106¶ 2x105
8x106¶ 2x105
Activation
FcγRIIIB‡ CD16B
FCGR3B
NA1,
NA2 or
SH
2x105
No
binding
1x106
No
binding
Decoy;
activation?
FcRn§
None
assigned
FCGRT
ND||
8x107¶
5x107¶
3x107¶
2x107¶
IgG recycling
and transport
TRIM21§
None
assigned
TRIM21
ND
5x106¶
5x106¶
2x106¶
5x106¶
Activation and
proteasome
targeting
ITAM
γ2
7¶
7¶
7¶
α
α
Immune complexes
Complexes of antigens that
are bound to antibodies and,
sometimes, components of
the complement system. The
concentration of immune
complexes is increased in
many autoimmune disorders,
in which the immune
complexes become deposited
in tissues and cause tissue
damage.
ITIM
α
α
Mononuclear phagocyte
system
(MPS). Bone marrow-derived
cells with different
morphologies (that is,
monocytes, macrophages and
dendritic cells) that are mainly
responsible for phagocytosis,
cytokine secretion and antigen
presentation.
γ2
α
GPI
anchor
Neonatal FcR
(FcRn). Unrelated to classical
Fc receptors (FcRs) and binds
to a different region in the
antibody Fc fragment. It is
structurally related to the
family of MHC class I molecules
and is responsible for
regulating IgG half-life.
Cross-presentation
The initiation of a CD8+ T cell
response to an antigen that is
not present within antigenpresenting cells (APCs). This
exogenous antigen must be
taken up by APCs and then
re‑routed to the MHC class I
pathway of antigen
presentation.
Monocyte-derived DCs
(moDCs). In vitro-generated
monocyte-derived DCs are
the most studied DC subset
and can be obtained in large
quantities by culturing mouse
bone marrow cells in
granulocyte–macrophage
colony-stimulating factor
(GM‑CSF), or by culturing
human peripheral blood
monocytes in GM‑CSF and
interleukin‑4 (IL‑4).
β2m α
β2m, β2-microglobulin; FcγR, Fc receptor for IgG; FcRn, neonatal FcR; GPI, glycosyl phosphotidylinositol; ITAM, immunoreceptor
tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; TRIM21, tripartite motif-containing
protein 21. *Gene polymorphisms identified either by the position in the protein and the amino acid substitutions (for example,
His131 or Arg131), or by the name of the allele (NA1, NA2 or SH). ‡Associates with integrins140. §Intracellular receptor50,52. ||No alleles
have been described to date that affect binding affinity or that are linked with disease. ¶Affinity value corresponding to a
high-affinity interaction. The binding affinity values of the FcγRs for the various immunoglobulin subclasses are depicted in M-1 unit.
also express FCGR2B mRNA, as well as that for the
activating FcγR FCGR2A. Both mouse and human
+
CD172α
cDCs |express
low levels of FcγRI, as deterNature Reviews
Immunology
mined by flow cytometry 21,27–29. These data suggest that
macrophages and moDCs express mRNA for most activating and inhibitory FcγRs, whereas cDCs and pDCs
mainly express mRNA for the inhibitory FcγRIIB.
Although mRNA expression does not always predict whether a protein is expressed or not, these mRNA
expression data are supported by recent human and
mouse flow cytometry data28,30–34. Of note, these data were
compiled from representative DC and tissue-resident
macrophage subsets in a limited number of tissues under
steady-state and disease conditions, and it remains to be
determined whether they are applicable to all situations.
However, Kupffer cells of the liver and osteoclasts also
express all activating FcγRs (REF. 35; M.G., unpublished
observations). Furthermore, it remains to be shown
whether particular cytokines or inflammatory mediators
can increase the expression of activating FcγR on cDCs.
There are some important similarities with respect
to FcγR expression between mice and humans (FIG. 1);
however, there are also some subtle but important differences in both species. Although mouse moDCs
and macrophages constitutively express high levels
of Fcgr1 mRNA in the steady state23,27,36,37, human cultured moDCs and macrophages express very low levels
of FCGR1 (REFS 28,38,39). This could be due to the use
of interleukin‑4 (IL‑4) in the human cultures, which is
known to downregulate FcγRI expression39–42. FcγRI
96 | FEBRUARY 2014 | VOLUME 14
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Table 2 | Mouse Fc receptors for IgG*
Structure
Name
Gene
IgG1
IgG2a
IgG2b
IgG3
Major function
FcγRI
Fcgr1
NB
1x10
1x10
+
Activation
FcγRIIB
Fcgr2b
3x106
4x105
2x106
No
binding
Inhibition
FcγRIII
Fcgr3
3x105
7x105
6x105
No
binding
Activation
FcγRIV
Fcgr4
NB
3x107¶
2x107¶
No
binding
Activation
FcRn§
Fcgrt
8x106
+
+
+
IgG recycling and
transport
TRIM21§
Trim21
2x106
+
+
+
Activation and
proteasome targeting
ITAM
γ2
5
‡
α
ITIM
8¶
α
α
γ2
α
β2m α
+, binds receptor but the binding affinity is unknown; β2m, β2-microglobulin; FcγR, Fc receptor for IgG; FcRn, neonatal FcR;
Nature
Reviews | Immunology
ITAM,
immunoreceptor
tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; TRIM21, tripartite
motif-containing protein 21. *The binding affinity values of the FcγRs for the various immunoglobulin subclasses are depicted
in M-1 unit. ‡Under debate151. §Intracellular receptor50,52. ¶Affinity value corresponding to a high-affinity interaction.
is highly expressed on human macrophages and moDCs
that have been directly isolated from inflamed tissues
(such as from tumour ascites from patients with cancer 43 or from the inflamed colon of patients with inflammatory bowel disease27). In addition, mouse pDCs do
not express activating FcγRs on their cell surface as
determined by flow cytometry 34, whereas human pDCs
express the activating FcγRIIA33,44, albeit at low levels
compared with monocytes and macrophages (for protein expression of FcγRIIA see REFS 33,44; for mRNA
expression see FIG. 1). FcγRIV is only present in mice,
and FcγRIIA, FcγRIIC and FcγRIIIB are only present in
humans. However, mouse FcγRIV has been suggested
to be the homologue of human FcγRIIIA40, and mouse
FcγRIII has been suggested to be the homologue of
human FcγRIIA (REF. 12; J. Lejeune and H. Watier, personal communication). Furthermore, as mouse FcγRIV
can also bind IgE, it was thought to be functionally
equivalent to the human IgE receptor FcεRI when it is
expressed on monocytes and macrophages15.
The difference in expression of activating FcγRs
between cDCs and moDCs is so striking that three
research groups have independently hypothesized that
expression of FcγRI, along with FcεRI, can be used as an
effective discriminative marker to separate moDCs and
macrophages from cDCs in mice and humans (BOX 2).
Throughout this Review, it is important to make a conceptual distinction between phagocytes found in the steady
state and those found in conditions of inflammation. The
cDCs that populate the peripheral tissues in homeostasis
mainly express the inhibitory FcγR and express low levels of activating FcγRs. Many pathogen encounters and
tissue ‘insults’ lead to neutrophil and monocyte recruitment into tissues. Monocytes can rapidly differentiate into
macrophages and moDCs in situ, and these cells express
almost all types of FcγRs. moDCs do not migrate well,
therefore it is difficult to envisage how they could function as antigen-presenting cells (APCs) for the naive
T cells that recirculate through the lymph nodes. However,
immunoglobulins only come into play a few days into the
primary immune response or during a memory response,
when primed T cells are poised to migrate to peripheral
tissues. Thus, we hypothesize that the main function of
activating FcγRs is to modify the encounter of moDCs
and T cells at sites of inflammation, and to promote the
clearance of pathogens in the periphery, as well as from
filtering areas in central lymphoid organs, by macrophages.
However, we do not exclude the possibility that particular
activation states may induce higher expression of activating FcγRs on cDCs and that this might induce cDCs to
respond to immune complexes in such environments.
This is an area of research that requires more attention.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | FEBRUARY 2014 | 97
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 2 | DC and macrophage subsets
XCR1+ conventional DCs
•Ontogeny: conventional dendritic cells (cDCs) that are derived from pre-cDCs and that depend on the transcription
factor basic leucine zipper transcriptional factor ATF-like 3 (BATF3)
•Mouse surface markers: these cells express XC-chemokine receptor 1 (XCR1) and DC natural killer lectin group
receptor 1 (DNGR1; also known as CLEC9A) in all tissues, and they differentially express CD8a, CD103 or CD207
depending on the tissue
•Human surface markers: these cells express XCR1, DNGR1 and BDCA3 (also known as CD141)
•Main function: the cross-presentation of antigen for the activation of effector CD8+ T cells
CD172α+ conventional DCs
•Ontogeny: cDCs that are derived from pre-cDCs and that depend on the transcription factor interferon-regulatory
factor 4 (IRF4)
•Mouse surface markers: these cells express CD172α (also known as SIRPα) in all tissues, and they express CD11b or CD4
depending on the tissue
•Human surface markers: these cells express CD172α and BDCA1 (also known as CD1c)
•Main functions: the induction of T helper 2 (TH2) or TH17 cells, and the promotion of humoral immune responses
Plasmacytoid DCs
•Ontogeny: derived from pre-plasmacytoid DCs and depend on the transcription factor E2.2
•Mouse surface markers: these cells express Siglec‑H, bone marrow stromal antigen 2 (BST2) and LY6C
•Human surface markers: these cells express BDCA2 and BDCA4
•Main function: the production of type I interferon (IFN) during viral infections
Monocyte-derived DCs
•Ontogeny: derived from monocytes
•Mouse surface markers: these cells express the high-affinity Fc receptor I for IgG (FcγRI) and the high-affinity Fc receptor
for IgE (FcεRI); LY6C expression is lost with time
•Human surface markers: these cells express FcεRI; FcγRI expression is upregulated on activation
•Main functions: the promotion of local T cell responses, enhancement of inflammation and production of chemokines
Macrophages
•Ontogeny: mostly of primitive origin but can be derived from monocytes during inflammation
•Mouse surface markers: these cells express F4/80, FcγRI and tyrosine protein kinase MER (MERTK)
•Human surface markers: these cells express CD68; expression of FcγRI is upregulated on activation
•Main functions: sentinel immune function, the elimination of pathogens and tissue homeostasis
Antigen internalization and degradation by FcγRs
Internalization of opsonized material or immune complexes represents the only function shared by all FcγRs that
are expressed at the cell surface, irrespective of whether
they have an ITAM or an ITIM. However, the molecular mechanisms that underlie this internalization are
different. The internalization of immune complexes via
ITAM-bearing FcγRs relies on the tyrosines of the ITAM
present in the FcγR complex 45, whereas the internalization of immune complexes via ITIM-bearing FcγRIIB
relies on the presence of a di‑leucine motif in its intracellular domain46. Importantly, although both receptor types
rapidly endocytose the receptor complex and its bound
ligands47, it is thought that the type of FcγR that mediates
the internalization influences the degradative pathway in
which the antigens will subsequently be routed. The model
suggests that internalization by activating FcγRs favours a
degradative route for antigen processing and presentation
that results in T cell activation, whereas internalization by
FcγRIIB favours a retention pathway that preserves the
intact antigen for subsequent transfer to B cells48. It was
recently shown that IgG opsonization enhances antigen
presentation to CD4+ T cells only when antigen and IgG
are present within the same phagosome; indeed, cells that
contain phagosomes with either antigen or IgG alone
failed to efficiently present antigens49. Therefore, a specific
mechanism may be responsible for the efficient routing of
internalized antigen when it is bound to an antibody and
internalized by an FcγR.
FcRn has been suggested to facilitate the transport
of IgG-bound antigens through particular intracellular
routes to favour antigen presentation and subsequent
immune responses50,51. FcRn is expressed by macrophages
and DCs in humans and mice and enables immune complex uptake and antigen processing by DCs3,52. FcRn is
also required for efficient phagocytosis of IgG-opsonized
bacteria by FcγRs53. Importantly, FcRn does not bind to
IgG at the physiological pH (that is, 7.4) of the extra­
cellular milieu, and only binds when histidine residues
in the Fc portion of IgG become protonated in the acidic
environment of endocytic vacuoles (that is, pH≤6.5)3.
Immune complexes bind to FcγRs on the surface of DCs
or macrophages, they are internalized and they subsequently bind to FcRn, which controls the intracellular
routing to antigen-processing endosomes 48,49 (FIG. 2)
and/or recycling endosomes. It is also possible that the
ubiquitously expressed intracellular receptor TRIM21
binds to IgG-opsonized (or IgM-opsonized) particles4
98 | FEBRUARY 2014 | VOLUME 14
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Human FcγR receptor expression
Classical Patrolling
monocyte monocyte Macrophage moDC
Activating FCGR1
pDC
XCR1+
cDC
CD172α+
cDC
Activating FCGR2A
Inhibitory FCGR2B
Activating FCGR2C
Activating FCGR3A
XCR1 +
cDC
Spleen
Skin
Blood
Skin
pDC
Blood
Blood
moDC
In vitro generated
Inflammation (ascites)
4 6 8 10 12 14
In vitro generated
Inflammation
Log2 expression
Alveolar
In vitro generated
Inflammation (ascites)
Blood
Blood
Decoy FCGR3B
Mouse FcγR receptor expression
Classical Patrolling
monocyte monocyte Macrophage
CD172α+
cDC
Activating Fcgr1
Inhibitory Fcgr2b
Activating Fcgr3
Spleen
Skin-draining lymph node
Lung
4 6 8 10 12 14
Spleen
Skin-draining lymph node
Log2 expression
Alveolar
Spleen
In vitro generated
Inflammation
Blood
Blood
Activating Fcgr4
Figure 1 | Compilation of microarray data of human and mouse FcγR expression
by DCs and macrophages. Expression values were extracted
from
published,
publicly
Nature
Reviews
| Immunology
available microarray data sets and represent log2 expression levels that were obtained
after quantile normalization of the data using the Robust Multi-array Average (RMA)
procedure (see Supplementary information S1 (figure)). Expression values were
subsequently colour-coded, varying from white (showing low expression), to orange
(showing medium expression) and to red (showing high expression). Note that low
mRNA expression levels do not necessarily correspond to no Fc receptor for IgG (FcγR)
expression; for example, the low mRNA levels of that encoding Fcγ receptor IIB (Fcgr2b) in
mouse plasmacytoid dendritic cells (pDCs) are sufficient for protein expression, as shown
by flow cytometry34. When merging microarray data from different platforms, data were
integrated at the gene level, keeping the probe sets that had the highest expression levels
when multiple probe sets were available. A final quantile normalization was then carried
out across all platforms and samples were aggregated and the median expression value
for each cell type was calculated. All mouse microarray data were obtained from the
publicly available Immunological Genome Consortium (REF. 145; NCBI gene expression
omnibus (GEO) data repository GSE15907), except for the monocyte-derived DC (moDC)
samples, which were obtained from REF. 146 (NCBI GEO data repository GSE2197) and
REF. 147 (NCBI GEO data repository GSE42101). Human microarray data were obtained
from REF. 43 (NCBI GEO data repository GSE40484) for monocytes, inflammatory
macrophages and inflammatory DCs; from REF. 30 (NCBI GEO data repository GSE35459)
for pDCs and conventional DCs (cDCs); from REF. 148 (NCBI GEO data repository
GSE18816) for alveolar macrophages; from REF. 149 (NCBI GEO data repository
GSE45466) for moDCs and from REF. 150 (NCBI GEO data repository GSE35433) for
monocyte-derived macrophages that were generated in vitro. Both of the methods used
for the array compilation, as well as the Fc receptor (FcR) expression data for additional
groups cells, including B cell, T cells, natural killer cells and neutrophils are included in
Supplementary information S1 (figure). XCR1, XC-chemokine receptor 1.
following internalization by FcRs that are expressed on
the cell surface (FIG. 2). The recognition of intracellular
antibodies by TRIM21 activates signalling pathways that
lead to cell activation and production of pro-inflammatory molecules54, and routes antibody-bound viruses to
the proteasome through its E3 ubiquitin ligase activity 5,55.
It is so far unclear whether TRIM21‑dependent signalling
pathways also affect the sorting of FcγR-internalized antigens (that is, not only of opsonized viruses) to particular
endosomal compartment routes.
The uptake through distinct FcγRs will influence
not only whether an antigen is presented or not but
also through which degradative pathway it is processed
and the repertoire of epitopes that is presented. In mice,
FcγRIIB expression was found to result in the presentation
of a restricted set of T cell epitopes compared with FcγRIII
expression. This difference relies on the ability of FcγRIII
to trigger the SYK signalling pathway and promote FcR
targeting to lysosomes56,57. In addition, the short intracytoplasmic domains of the human activating receptors FcγRI
and FcγRIIIA contain serine or threonine phosphorylation motifs that have been reported to regulate internalization (and phagocytosis) efficiency 58,59. There are several
isoforms of the inhibitory FcγRIIB in humans and mice
that have different antigen internalization and presentation properties6. A systematic analysis of the degradative pathways and T cell repertoire generation following
antigen internalization by each FcγR that is expressed by
macrophages and DCs remains to be carried out.
Role of FcγRs in phagocyte activation
In addition to facilitating the capture and the internalization of antibody-bound antigens or pathogens, most
FcγRs induce ITAM- or ITIM-mediated intracellular
signalling. This signalling strongly influences core functions of both macrophages and DCs, including their
functional polarization, their capacity to kill pathogens
and their regulation of T cell responses. Through concomitant expression of both activating FcγRs and the
inhibiting FcγRIIB, the immune system can set strict
thresholds for phagocyte activation.
Modulation of macrophage polarization. Macrophages
have been conceptually separated into classically activated
macrophages (M1 macrophages, which are activated by
IFNγ and are specialized for pathogen killing) and alternatively activated macrophages (M2 macrophages, which
are activated by IL‑4 and/or IL‑13 and are specialized for
tissue remodelling). Although crosslinking of activating FcγRs on monocytes and macrophages induces the
production of several pro-inflammatory cytokines and
chemokines60,61, immune complex‑mediated signalling
via activating FcγRs together with Toll-like receptor
(TLR) triggering induces a specific M2 activation state
in macrophages — macrophages in this state were termed
‘M2b’ or ‘regulatory’ macrophages. These cells produce
low levels of IL‑12 and high levels of IL‑10, tumour
necrosis factor (TNF), IL‑1 and IL‑6 (REFS 62–64).
Importantly, such combined signalling of FcγR and
TLR triggering leads to lower IL‑12 production than TLR
triggering alone in mouse macrophages62.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | FEBRUARY 2014 | 99
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Virus
Immune
complex
IgG
FcγR
Antigen
Common
γ-chain
ITAM
SYK
Internalization
and sorting
Increased
endosomal
maturation
FcRn
β2m
Processed
antigen
Late acidic endosome
moDCs
?
Protection from
degradation
TRIM21
Proteasome
Early endosome
Peptides
MHC class II
loading in the MIIC
MHC class I
loading in the ER
Signal 1:
Presentation
to CD4+ T cells
Signal 1:
Cross-presentation
to CD8+ T cells
Figure 2 | Efficient processing of antibody-coating antigens by moDCs. Triggering of Fc receptors for IgG (FcγRs)
on monocyte-derived DCs (moDCs) induces a more efficient immunoreceptor tyrosine-based
activation
Nature
Reviewsmotif
| Immunology
(ITAM)-dependent uptake of the antigen. Moreover, signalling through the activating FcγRs via spleen tyrosine kinase
(SYK) activates moDCs and facilitates endosomal maturation, increased lysosomal fusion and efficiently facilitates
the delivery of processed antigens to the MHC class II compartment (MIIC) for enhanced MHC class II presentation to
CD4+ T cells. In addition, antigens coupled to antibodies are more efficiently cross-presented than unbound antigens.
This is thought to be the result of two independent mechanisms: first, neonatal FcRn (FcRn)-mediated protection from
degradation and efficient delivery of the antigen to the cytosol; and second, tripartite motif-containing protein 21
(TRIM21)-mediated increased delivery to the proteasome. Note that TRIM21‑mediated delivery to the proteasome
has been shown to occur for opsonized particles (including viruses), but not directly for antigen-containing immune
complexes (question mark). TRIM21 also functions in the absence of activating FcγRs54 (dashed arrows). However,
uptake of antibody-coated viruses via FcγRs may help target them to TRIM21. In addition, all of these experiments
were carried out in moDCs and it is currently unknown whether these observations also apply to conventional DCs.
β2m, β2-microglobulin; ER, endoplasmic reticulum.
The activation of macrophages by immune complexes is determined by the balance between the triggering of activating ITAM-bearing FcγRs and the triggering
of inhibitory ITIM-bearing FcγRIIB. The antigen size,
concentration and IgG valence in the immune complex
could be additional factors that influence macrophage
activation. Macrophages from Fcgr2b–/– mice have a
lower activation threshold than macrophages from wildtype mice and these deficient mice are much more sensitive to immune complex‑induced alveolitis65, arthritis66
and sepsis67. However, Fcgr2b–/– mice are more resistant
to pneumococcal peritonitis because of the increased
ability of their macrophages to clear the bacteria67, and
transgenic overexpression of FcγRIIB on macrophages
increased mortality after Streptococcus pneumoniae
infection68. Taken together, this shows that the increased
macrophage activation that is found in the absence of
FcγRIIB can be beneficial for the host as it increases the
ability of macrophages to clear bacteria, but it can also be
detrimental when it increases immunopathology.
100 | FEBRUARY 2014 | VOLUME 14
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Antibody-mediated regulation of macrophage infection.
Many pathogens have developed escape mechanisms to
inhibit phagolysosomal fusion, and thus degradation,
in order to survive in the hostile intracellular environment of macrophages. Legionella pneumophila and
Toxoplasma gondii can evade phagolysosomal fusion
and can reside within vacuoles that are permissive for
replication69,70. However, as mentioned above, the presence of specific antibodies on the surface of the pathogens redirects these pathogens to lysosomes, which
inhibits intracellular replication and facilitates efficient
elimination by macrophages71. This process requires the
expression of activating FcγRs, which target the bacteria
to the lysosomes following uptake. Similarly, the absence
of FcγRIIB on Mycobacterium tuberculosis-infected
macrophages induces increased IL‑12 production and
increased resistance to infection, whereas the absence
of the FcR common γ‑chain is associated with increased
susceptibility to infection72. The delivery of pathogens
to macrophages and the concomitant activation of these
cells could represent one of the major mechanisms that
underlies the protective function of antibodies against
intracellular pathogens73.
However, delivering pathogens to macrophages is not
always favourable for the host. The long-lived nature of
macrophages74–77 may be an explanation for why these
cells represent an attractive niche for pathogens that
induced chronic infections. Increased uptake of such
opsonized macrophage-tropic microorganisms through
FcγRs may therefore result in antibody-enhanced infection. This can occur via increased uptake of the pathogen
or by subversion of macrophage activation78; for example, antibodies against dengue virus facilitate its uptake
by macrophages79. When the level of maternal dengue
virus-specific antibodies in young infants is below the
protective level for neutralization but still high enough
to mediate antibody-enhanced infection, these antibodies increase the infectivity and the severity of the illness80.
Therefore, it has been suggested that antibody-enhanced
infection is the main mechanism to explain why, during a
dengue virus epidemic in Cuba in 1981, children that had
been previously infected presented more severe forms of
the infection than children that were too young to have
been infected during the epidemic of 1977 (REF. 81).
Another mechanism of antibody-enhanced infection involves subversion of macrophage activation.
Leishmania major is a macrophage-tropic pathogen that
has developed escape mechanisms to ensure its intracellular survival82. A polarized T helper 1 (TH1)‑type
immune response has been associated with enhanced
parasite clearance through the induction of M1 macrophages, whereas a TH2‑type response has been associated with host susceptibility through the induction of
M2 macrophages. Engagement of ITAM-bearing FcRs
on macrophages activates the mitogen-activated protein
kinase (MAPK) pathway through SYK and induces the
downregulation of IL‑12 and the upregulation of IL‑10
production by M2b macrophages. Leishmania amazonensis parasites that are coated with immunoglobulins
induce IL‑10 production by macrophages from wildtype mice but not by those from mice that are deficient
for all activating IgE and IgG receptors83. Furthermore,
these activating IgE and IgG receptor-deficient mice
were more resistant to Leishmania spp. infection84–86.
Taken together, these observations show that the expression of FcRs on macrophages influences both the uptake
of pathogens by these cells and the concomitant activation of the cells (FIG. 3), which is ultimately an important
factor that influences the outcome of infectious diseases.
Role of FcγRs in DC activation
Modulation of antigen presentation by FcγRs. Several
studies have shown that antibody-bound soluble antigens, particulate antigens or apoptotic tumour cells
enable DCs to activate antigen-specific T cells more
efficiently than free antigens45,87–92, which implies that
FcγRs have a crucial role in augmenting antigen presentation (FIG. 2). In mice, experiments have been carried out
in vitro on granulocyte–macrophage colony-stimulating
factor (GM‑CSF)-cultured moDCs or in vivo by injecting
immune complexes composed of model antigens such
as ovalbumin (OVA) complexed with OVA-specific IgG
(often IgG raised in rabbits). Although both CD4+ and
CD8+ T cell responses can be increased by immune complexes, there seems to be a bias for CD8+ T cell responses,
as immune complexes mainly enter cross-presentation
pathways87,93–95. Studies using mice in which DCs can be
conditionally depleted (Cd11c–DTR (diphtheria toxin
receptor) mice) have revealed that antigen presentation
in response to immune complex injection depends on a
CD11chi cell, which is probably a DC96.
Although both inhibitory FcγRIIB and activating
FcγRs can mediate the uptake of antigens from immune
complexes (see above), it seems that it is mainly activating FcγRs that promote antigen presentation, which
is due to their ability to activate DCs and to stimulate
the MHC class I cross-presentation machinery 93,97. The
precise activating FcγR that is involved in mediating
the immunopotentiating effects of immune complexes,
as well as the precise subtype of DC that controls the
immune response following the in vivo injection of
immune complexes, is unknown. However, given the
low expression levels of FcγRs on cDCs in the steady
state, it is questionable whether these cells are the ones
that mediate this effect in vivo98.
The presence of immune complexes does not increase
the capacity of XCR1+ cDCs to cross-present antigens89
and the probable explanation for this is that XCR1+ cDCs
already express receptors that favour cross-presentation,
so the presence of a specific antibody does not enhance
their already high cross-presentation capacity 89. Early
studies suggested that splenic CD172α+ cDCs (identified originally as CD8α− DCs) cross-present immune
complex‑associated antigens more efficiently than soluble antigens. It is worth noting that in these early studies
there was no clear distinction between CD172α+ cDCs
and moDCs (both of which are CD8α−CD11b+CD172α+).
However, if these cells were indeed CD172α+ cDCs,
then this increased cross-presentation would have to
occur through FcγRIIB, as this is the only FcγR that is
highly expressed by these cells in mice (FIG. 1). In fact, the
increased cross-presentation was shown to depend on
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | FEBRUARY 2014 | 101
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
a FcγR function in macrophages
Opsonized infected cell
• Increased uptake
• Lysis of target cell
• ADCC
FcγR
Opsonized pathogen
• Increased uptake
• Phagolysosomal fusion
• Pathogen killing
+ TLR ligand
IVIG therapy
• Induces increased inhibitory
FcγRIIB expression
• Induces decreased activating
FcγR expression
• Increases the activation threshold
b FcγR function in pDCs
Immune complexes
• Increased IL-10 production
• Decreased IL-12 production
• High IL-1, IL-6 and TNF production
• M2b (regulatory) activation state
Antibody-enhanced infection
• Macrophage-tropic pathogens
• Increased uptake
• Increased IL-10 production
• Pathogen persistence
Particulate antigens
• Poor antigen uptake
• Poor antigen processing
• No antigen presentation
Autoantibody
Self DNA
Chromatin
Immune complexes
• Increased antigen uptake
• Antigen routing to MHC
class II-processing organelles
• Antigen presentation to
CD4+ T cells
• Immune tolerance?
Antimicrobial
peptide
FcγRIIA
FcγRIIB
HMGB1
Self DNA-containing immune complexes
• Phagosomal maturation
• Generation of ISC
• TLR9 relocalization to the ISC
• High type I IFN production
• Autoimmunity (SLE)
Figure 3 | FcγR-mediated macrophage and pDC activation. a | Pathogens coated with antibodies (opsonized pathogens)
Nature activation
Reviews | Immunology
are often more efficiently killed by macrophages because of the Fc receptor for IgG (FcγR)-mediated
of
macrophages, which induces an immunoreceptor tyrosine-based activation motif (ITAM)-dependent increased uptake and
increases phagolysosomal fusion, thereby yielding more efficient killing of pathogens. Similarly, opsonized infected cells
can be killed through a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC). However, immune
complexes induce a particular macrophage activation status termed the M2b (regulatory) macrophage activation state,
which is characterized by increased interleukin‑10 (IL‑10) production and decreased IL‑12 production, but high IL‑1, IL‑6
and tumour necrosis factor (TNF) production. This M2b activation state can facilitate the survival of macrophage-tropic
pathogens, such as Leishmania spp., that have developed strategies to subvert macrophage function and to use the
macrophage as a preferential cellular niche. Increased uptake of these macrophage-tropic pathogens results in
antibody-enhanced infection. Finally, the manipulation of macrophage activation by immune complexes has been
suggested to be one of the main mechanisms that underlies intravenous immunoglobulin therapy (IVIG therapy). A high
dose of immune complexes is thought to induce higher expression of inhibitory FcγRIIB and lower expression of the
activating FcγRs, which yields an increased activation threshold for macrophages. b | Plasmacytoid dendritic cells (pDCs)
have poor capacities to capture and present particulate antigens to CD4+ T cells compared with conventional DCs (cDCs)
(dashed arrow). Antibody-coated antigens are more efficiently taken up by pDCs and subsequently more efficiently routed
to MHC class II‑processing organelles compared with cDCs, which results in better antigen presentation to CD4+ T cells.
As pDCs have been shown to be tolerogenic in the steady state, we hypothesize that, in the absence of danger signals,
FcγR-mediated uptake and presentation of immune-complexed antigens by pDCs induces the development of immune
tolerance. pDCs have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In patients with SLE,
self DNA-containing immune complexes that are associated with antimicrobial peptides, high-mobility group box 1 protein
(HMGB1) and autoantibodies are recognized by FcγRs on pDCs. This triggers phagosomal maturation and the generation of
the interferon (IFN) signalling compartment (ISC). Triggering of FcγRs by self DNA-containing immune complexes has been
shown to be crucial in the relocalization of Toll-like receptor 9 (TLR9) to the ISC, which then results in high levels of type I IFN
production by the pDCs and exacerbates the autoimmune response in patients with SLE.
102 | FEBRUARY 2014 | VOLUME 14
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
the expression of the FcR common γ-chain89, which
implicates the involvement of an activating FcγR rather
than FcγRIIB, and thus the involvement of moDCs
rather than cDCs, in this process. Studies in vitro using
GM‑CSF-cultured mouse moDCs have shown that both
FcγRI and FcγRIII contribute to the enhanced antigen
presentation of immune complexes, but the precise role of
FcγRIV remains to be determined99. Injection of immune
complexes in mice might cause a mild form of inflammation (due to complement activation or to contaminating
endotoxin), which would lead to the recruitment and the
activation of moDCs. Although direct proof of this scenario is lacking so far, we hypothesize that the injection
of immune complexes increases cross-presentation of the
complexed antigens, mainly through the recruitment and
the activation of moDCs via ITAM-bearing FcγRs, rather
than through cDCs.
In humans, the presence of antigens in immune complexes also favours cross-presentation by moDCs, and
the FcγR that is involved was shown to be activating
FcγRIIA, although cross-presentation may be counteracted by the inhibitory FcγRIIB28,100,101. FcγRI was not
suggested to be involved. However, as IL‑4 is used to
generate human moDCs in vitro, and as IL‑4 induces
the rapid downregulation of FcγRI by moDCs40–42, the
use of in vitro-generated moDCs may underestimate the
importance of FcγRI as an internalization and activating receptor for human moDCs. In human monocytes,
FcγRI targets antigens to the MHC class II‑rich late
endosomes and leads to enhanced antigen processing
and presentation to CD4+ T cells102.
Considering the studies of antigen uptake and processing as a whole, we conclude that activating FcγRs on
DCs promote antigen presentation to CD4+ and CD8+
T cells. The inhibitory FcγR, possibly in combination
with FcRn, on cDCs and pDCs can also promote antigen
presentation on MHC class II molecules and preserves
some intact antigens for presentation to B cells. The regulated expression of FcγRs by different APC subsets further amplifies the specialized function of DCs to process
antigens and of macrophages to degrade antigens.
Group 2 innate lymphoid
cells
These cells predominantly
produce type 2 cytokines
and require the transcription
factors retinoic acid
receptor-related orphan
receptor‑α (RORα) and
GATA-binding protein 3
(GATA3) for their development
and function.
Polarization of adaptive immune responses. T cell
polarization is a crucial aspect of immune regulation and
is controlled by APCs providing instructive signals to
naive T cells in the draining lymph nodes and the spleen.
Whether a particular APC instructs naive TH cell differentiation depends on the migratory capacity of the APC
and its potential to produce co‑stimulatory molecules and
instructive cytokines that influence the T cell differentiation programme. Most experiments that investigate the
influence of FcγR triggering on TH cell polarization
have been carried out in vitro using mouse or human
GM‑CSF-generated moDCs, or in vivo after the artificial
introduction of immune complexes in naive mice.
There are a few conceptual problems when discussing
how FcγR triggering on APCs influences naive TH cell
polarization in normal physiology, as high-affinity antibodies and immune complexes only form when adaptive
immunity has already been induced. However, natural
antibodies are present in unimmunized mice and have a
broader and lower affinity specificity that might trigger
FcγRs during a naive T cell response. Moreover, we and
others have recently shown that the main DCs that are
responsible for the initial induction of T cell responses
are migratory cDCs21,23,103, but these cells express very
low levels of activating FcγRs. MoDCs express the highest levels of activating FcγRs, but are much more sessile
cells that primarily reside within the inflamed tissues23,36.
Therefore, FcγR-mediated triggering of DCs would
mainly affect the interactions between primed T cells
and moDCs in peripheral tissues to maintain TH cell
polarization that is initiated by cDCs104,105. Signalling
through ITAM-containing activating FcγRs can upregulate the expression of co‑stimulatory receptors (the
so‑called signal 2) and the production of TH1‑polarizing
cytokines (the so‑called signal 3) (FIG. 4). Indeed, when
immune complexes were injected in vivo to promote
tumour immunity, or when responses to opsonized
Leishmania spp. were studied in naive mice, there was
an increase in the number of IFNγ-producing CD4+ TH1
cells, accompanied by an increased production of IL‑12
by DCs95,106,107. The triggering of activating FcγRs on
human moDCs can also promote DC activation and can
lead to increased antigen uptake, processing and presentation, and to TH1 cell polarization61. This response
probably involves the induction of a type I IFN response
(FIG. 4), as small interfering RNA (siRNA)-mediated
inhibition of the gene encoding signal transducer and
activator of transcription 1 (STAT1), which is downstream of the type I IFN receptor, inhibited the upregulation of the co-stimulatory receptors CD80 and CD86,
which are markers of DC activation61.
However, other groups have found that targeting
antigens to activating FcγRs promotes the development
of TH2‑type immune responses97,108. In mouse models of
asthma, which are driven by type 2 cytokines, triggering
of FcγRI or FcγRIII on DCs has been shown to induce
the production of IL‑10 and to skew T cell immunity
towards the TH2 cell phenotype108,109. In addition, when
primed OVA-specific TH2 cells were transferred to mice,
OVA-containing immune complexes activated T cells
much better than antigen alone110. The triggering of
FcγRIII and TLR4 on lung DCs induced the production
of IL‑33. IL‑33 signals through its receptor (which consists of ST2 and IL‑1 receptor accessory protein) that is
expressed by TH2 cells, group 2 innate lymphoid cells, basophils, natural killer T cells and DCs to promote a type 2
immune response111 — in mice, this leads to the generation of IgG1 and IgE antibodies. FcγRIII can be triggered
not only by IgG1‑containing immune complexes but also
by IgE. Furthermore, the crosslinking of IgE on moDCs
was shown to suppress IL‑12 production and to increase
IL‑10 production in an FcγRIII-dependent manner 112.
However, how FcγR triggering on DCs affects TH cell
polarization still needs further study.
Role of the inhibitory FcγR on DCs. Our review of
published studies showed that inhibitory FcγRIIB is
expressed by all macrophages and DC subsets (FIG. 1)
and is the predominant FcγR that is expressed by cDCs
and pDCs. As in many cell types, triggering of FcγRIIB
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | FEBRUARY 2014 | 103
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
on DCs has the potential to suppress the effects that are
mediated by activating FcγRs. Mice that lack FcγRIIB
generally mount an exaggerated T cell response following
the injection of immune complexes, and gene expression
profiling of moDCs showed exaggerated DC activation
when this receptor was absent 96,113. Furthermore, mice
that selectively lack FcγRIIB on DCs showed enhanced
T cell responses to injection of immune complexes
in vivo93. Targeting of antigens to FcγRIIB might also
be necessary for maintaining tolerance to self antigens
that are derived from apoptotic cells114, but it remains to
be shown whether mice that specifically lack FcγRIIB
on DCs develop signs of autoimmunity. The induction of mucosal tolerance leads to the generation of
IgG-containing immune complexes in the nasal draining lymph nodes, which was shown to be suppressed in
FcγRIIB-deficient mice because of a failure to induce the
development of CD4+CD25hi regulatory T (TReg) cells115.
The maturation of human moDCs is accompanied
by the downregulation of FcγRIIB expression, which
hence lowers their immunoglobulin-mediated activation threshold38,101. When this receptor was blocked,
moDCs were shown to produce more IL‑12p70 and to
induce more T cell proliferation in response to immune
complex‑mediated stimulation61. Triggering of FcγRIIB
also subverted the normal activation of DCs by the TLR4
agonist lipopolysaccharide116. In addition, triggering of
FcγRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes in vitro in the presence of immune complexes, their
differentiation is hampered and they no longer produce
IL‑12 in response to TLR4 agonists117.
Furthermore, the important role that FcγRIIB has in
regulating DC responsiveness to immune complexes is
supported by the fact that its expression relative to that
of activating FcγRs is tightly regulated. Type 2 cytokines
(including IL‑4, IL‑10 and transforming growth factor-β
(TGFβ)) increase FcγRIIB expression by moDCs101,118,119,
whereas type 1 cytokines (including IFNγ and
TNF) decrease FcγRIIB expression by moDCs120,121.
Conversely, IFNγ also increases human FcγRI expression and mouse FcγRIV expression by monocytes,
whereas TGFβ and IL‑4 decrease the expression of these
FcγRs40,41. Taken together, these observations show that
the cytokine milieu can influence the expression of both
activating FcγRs and FcγRIIB, and hence can modulate
the threshold for moDC maturation.
Role of FcγRs on pDCs. pDCs are an important source
of early type I IFN and have the capacity to crosspresent exogenous antigens to CD8+ T cells as efficiently
as XCR1+ cDCs, despite having a lower uptake of antigens122. However, in humans and mice, pDCs do not present exogenous antigens well to CD4+ T cells. pDCs that
have been isolated from patients undergoing clinical DC
therapy for melanoma were cultured in vitro and the antigen keyhole limpet haemocyanin (KLH), to which there
was no prior exposure, was added to the cultures for the
purpose of immunomonitoring the induction of T cell
immunity. These pDCs could only present KLH antigen
to KLH-specific CD4+ T cells when serum containing
Immune
complex
FcγR
IgG
Antigen
IFNAR
Type I IFN
ITAM
SYK
BTK
LAT
PLCγ
IRF3–
IRF7
PI3K
JAK
?
AKT
PKC
MAPK
STAT1
NF-κB
Signal 3:
Polarizing cytokines
Signal 2:
Co-stimulatory receptors
Figure 4 | Role of FcγRs in moDC
maturation. 
Triggering
Nature
Reviews | Immunology
of Fc receptors for IgG (FcγRs) on monocyte-derived
dendritic cells (moDCs) induces immunoreceptor
tyrosine-based activation motif (ITAM)-dependent DC
maturation and increases T cell responses. On the one
hand, ITAM-mediated signalling via spleen tyrosine kinase
(SYK) and other signalling intermediary molecules, as
depicted, induces the expression of co‑stimulatory
molecules, which yields a better signal 2; on the other
hand, ITAM-mediated signalling induces the production of
polarizing cytokines, which induces an optimal signal 3.
Note that it is currently not clear whether FcγR-mediated
signalling drives a particular type of T cell response (that is,
T helper 1 (TH1), TH2, TH17, T follicular helper (TFH) or
regulatory T (TReg) cell response). In addition, all of these
experiments were carried out on moDCs and it is currently
unknown whether these observations also apply to
conventional DCs. Question mark indicates this pathway
has been proposed but not formally demonstrated.
Dashed line indicates there are additional steps in this
pathway. BTK, Bruton’s tyrosine kinase; IFN, interferon;
IFNAR, type I IFN receptor; IRF, interferon-regulatory
factor; JAK, Janus kinase; LAT, linker for activation of T cell;
MAPK, mitogen-activated protein kinase; NK-κB, nuclear
factor-κB; PI3K, phosphoinositide 3‑kinase; PKC, protein
kinase C; PLCγ, phospholipase Cγ; STAT1, signal transducer
and activator of transcription 1.
antigen-specific antibodies was added to the culture. The
serum facilitated KLH antigen uptake in endosomes in a
process that required FcγRIIA123. KLH uptake was inhibited by TLR9 ligands that accumulate in late endosomes,
but not by TLR9 ligands that target early endosomes,
suggesting that the immunoglobulin-mediated processing of KLH occurred in late acidic endosomes, which are
sites of MHC class II loading 124. Furthermore, transgenic
104 | FEBRUARY 2014 | VOLUME 14
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Intravenous
immunoglobulin therapy
(IVIG therapy). Injection of high
doses of polyclonal antibodies
into patients.
overexpression of the activating human FcγRIIA boosted
the uptake of immune complexes by mouse pDCs34.
In addition, mouse pDCs only present soluble OVA to
CD4+ T cells in the presence of OVA-containing immune
complexes. Mouse pDCs mainly express FcγRIIB, and
blocking antibodies against this receptor blocked antigen
routing to MHC class II‑processing organelles and the
subsequent induction of CD4+ T cell proliferation107,125.
Why exactly mouse pDCs use inhibitory FcγRIIB whereas
human pDCs use activating FcγRIIA remains to be investigated. Both mouse and human pDCs are known to promote the generation of TReg cells that mediate peripheral
tolerance and that suppress tumour immunity; however,
it remains to be investigated whether targeting immune
complexes to pDCs in the steady state promotes the
induction of tolerance.
Although pDCs control tolerance in the steady state,
their activation during immune complex uptake might
break tolerance and contribute to autoimmunity. pDCs
have been implicated in the pathogenesis of systemic
lupus erythematosus (SLE), which is a multisystem autoimmune disorder characterized by autoantibodies that
are specific for nuclear components, including chromatin
and double-stranded DNA (dsDNA)126. The recognition
of bacterial DNA occurs via endosomal TLR9 and in normal conditions self DNA is not recognized by this receptor. However, in patients with SLE, immune complexes
that consist of autoantibodies, self DNA, high-mobility
group box 1 protein (HMGB1) and neutrophil-derived
peptides trigger the production of type I IFN by pDCs in
a process that requires FcγRIIA and TLR9 (REFS 44,127).
The triggering of TLR9 occurs in a late endosomal
compartment termed the IFN signalling compartment (ISC), which contains the signalling adaptor TNF
receptor-associated factor 3 (TRAF3), which thus leads
to the induction of IFN-regulatory factor 7 (IRF7) and
a type I IFN response. For TLR9 to traffic to the ISC,
it first needs to traffic from the endoplasmic reticulum
to the phagosome — a process that requires UNC93
homolog B (UNC93B). DNA-containing immune complexes stimulate the localization of TLR9 and UNC93B to
phagosomes in a process that requires FcγRs. Strikingly,
triggering of FcγRs by DNA-containing immune complexes also induces the recruitment of the autophagy
protein LC3 and autophagy-related protein 7 (ATG7)
to the phagosome, phagosomal maturation and the trafficking of TLR9 to the ISC compartment 128. Therefore,
IFNα secretion by pDCs in response to DNA-containing
immune complexes depends on a convergence of
phagocytic and non-canonical autophagic pathways.
Pathogens can also activate pDCs and this response
could be influenced by FcγR triggering. The IFNα
response to Staphyloccocus aureus in human pDCs has
been shown to occur only in the presence of specific antibodies that trigger FcγRIIA, which facilitates the activation
of TLR9 by bacterial DNA and thus represents a memory
response129. Targeting of CpG oligodeoxynucleotides to
FcγRIIA, which is selectively expressed by pDCs), has
been suggested to be a valuable pDC activation strategy for
human immunotherapy of cancer130. In humans, FcγRIIA
seems to be the dominant receptor for enhancing pDC
responsiveness to TLR9 agonists. There are some important differences in mice. In mice, TLR9 is expressed not
only by pDCs, but also by other DC subsets and macro­
phages. Moreover, FcγRIIA is not expressed in mice
and many functions of human FcγRIIA are mediated by
FcγRIII, which is also expressed by DCs and macrophages.
The exact cell type responding to DNA‑containing
immune complexes131 has yet to be defined.
Therefore, in mice and in humans, pDCs can acquire
the capacity to present antigens to CD4+ T cells when
these antigens are bound to immune complexes and
internalized through FcγRs. Although this pathway is
probably involved in mediating tolerance in the steady
state, concomitant exposure to TLR ligands or microbial
products might promote effector T cell immunity and
might cause disease.
Clinical implications
The fact that FcγR signalling can influence DC and
macrophage activation has important clinical applications. Modulating the ability of a therapeutic antibody
to bind to activating versus inhibitory FcγRs could tip
the balance in favour of cellular activation or suppression. Cellular activation is desirable for cancer immuno­
therapy or for vaccination against infectious diseases,
whereas suppression is necessary for the induction of
immune tolerance in cases of chronic inflammation and
autoimmunity. Adoptive DC therapy using autologous
moDCs or pDCs might be greatly facilitated by targeting antigens to activating FcγRs, particularly when the
inhibitory FcγR is also blocked. The feasibility of this
concept has been shown in preclinical mouse models93,132
and in human ex vivo studies28,61,123.
Intravenous immunoglobulin therapy (IVIG therapy)
has been used to treat various autoimmune diseases,
although the precise mechanism that underlies its
protective effect is still under debate 133. It has been
suggested that injection of a high dose of IgGs would
simply compete with the immune complexes that are
present in many autoimmune diseases for binding to
individual FcγRs. However, IVIG does not function
in FcγRIIB-deficient mice134–136, which suggests that
IVIG does not simply compete for binding to activating
ITAM-bearing FcRs. IVIG was shown to increase the
expression of FcγRIIB and to decrease the expression of
FcγRIV on effector macrophages within arthritic lesions
and inflamed kidneys134,137. This may be one of the crucial immunomodulatory mechanisms that is induced by
IVIG, as IVIG increases the threshold for macrophage
activation. Importantly, the effect of IVIG seems to be
independent of FcγRIIB expression at the initiation of
the immune response, but requires FcγRIIB expression
on macrophages within the inflamed tissues138. Indeed,
the in vitro treatment of spleen cells from both wild-type
and FcγRIIB-deficient mice with immunoglobulins followed by the transfer of these cells to wild-type mice
could reproduce the beneficial effects of IVIG138. CD11c+
cells but not CD11c– cells were found to be the main
cells responsible for this beneficial effect, which suggests
that there is a role for DCs in the initiation of IVIGinduced immunosuppression. As inhibitory FcγRIIB
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | FEBRUARY 2014 | 105
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
does not seem to be involved in the initiation of this
immunosuppression, and as splenic mouse cDCs do
not express marked levels of the activating FcγRs (FIG. 1),
it is probable that the moDCs that are induced by the
immuno­globulin treatment are the main CD11c+ cells
responsible for this IVIG effect. Indeed, the transfer of
in vitro immunoglobulin-treated moDCs was sufficient
to protect mice from immunothrombocytopenia138.
Thus, IVIG seems to function through distinct FcγRs
on several cell types in different locations and at different time points; through activating FcγRs on moDCs
in the spleen during the initiation phase of the immune
response, thereby imprinting a tolerogenic phenotype on
these cells (possibly by inducing high IL‑10 production
by these cells); and by increasing FcγRIIB expression on
macrophages within the inflamed tissue, thereby increasing the threshold of macrophage activation during the
effector phase of the immune response. Human moDCs
that had been treated with IVIG in vitro also showed
increased IL‑10 production, decreased IL‑12 production
and impaired maturation139. The mechanism by which
IVIG-triggered moDCs may influence FcγRIIB expression on inflammatory macrophages may involve the
induction of a TH2‑type response140. Indeed, moDCs that
have been stimulated with immunoglobulins produce
IL‑33 (REF. 112), which in turn could induce the production of IL‑4, leading to an increase in the expression of
FcγRIIB on macrophages. Although the conversion of
moDCs into TH2‑type response-inducing cells in some
mouse studies was suggested to occur through FcγRIII108,
in humans this may occur through the C‑type lectin
DC‑specific ICAM3‑grabbing non-integrin (DC-SIGN;
also known as CD209), which also functions as a receptor
for sialic acid-rich IgG glycoforms. Indeed, IVIG treatment of transgenic mice that express human DC-SIGN
results in the IL‑33‑mediated induction of IL‑4 production by basophils, which in turn increases the expression
of FcγRIIB by macrophages in arthritic lesions140. FcRn
Jönsson, F. & Daëron, M. Mast cells and company.
Front. Immunol. 3, 16 (2012).
2. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as
regulators of immune responses. Nature Rev.
Immunol. 8, 34–47 (2008).
3. Roopenian, D. C. & Akilesh, S. FcRn: the neonatal
Fc receptor comes of age. Nature Rev. Immunol. 7,
715–725 (2007).
4. James, L. C., Keeble, A. H., Khan, Z., Rhodes, D. A. &
Trowsdale, J. Structural basis for PRYSPRY-mediated
tripartite motif (TRIM) protein function. Proc. Natl
Acad. Sci. USA 104, 6200–6205 (2007).
5.Mallery, D. L. et al. Antibodies mediate intracellular
immunity through tripartite motif-containing 21
(TRIM21). Proc. Natl Acad. Sci. USA 107,
19985–19990 (2010).
6. Daëron, M. Fc receptor biology. Annu. Rev. Immunol.
15, 203–234 (1997).
7. Blank, U., Launay, P., Benhamou, M. &
Monteiro, R. C. Inhibitory ITAMs as novel regulators of
immunity. Immunol. Rev. 232, 59–71 (2009).
8.Amigorena, S. et al. Cytoplasmic domain
heterogeneity and functions of IgG Fc receptors in
B lymphocytes. Science 256, 1808–1812 (1992).
9. Ono, M., Bolland, S., Tempst, P. & Ravetch, J. V.
Role of the inositol phosphatase SHIP in negative
regulation of the immune system by the receptor
FcγRIIB. Nature 383, 263–266 (1996).
10. Daëron, M., Jaeger, S., Du Pasquier, L. & Vivier, E.
Immunoreceptor tyrosine-based inhibition motifs: a
quest in the past and future. Immunol. Rev. 224,
11–43 (2008).
1.
has also been suggested to be important in one of the
mechanisms that underlie the protective action of IVIG
in K/BxN mice, which are a model for autoimmune
arthritis141.
Concluding remarks
During an adaptive immune response, the direct binding of immunoglobulins to FcγRs or the formation of
immune complexes containing specific antigens provide an important source of feedback that controls the
function of APCs. The outcome of this feedback can be
the enhanced phagocytic function of macrophages or it
can involve the increased targeting of antigens to DCs
that have become more proficient in antigen uptake and
processing, and in polarizing TH cell responses to the
pathogen. In addition, during repeated antigen encounter, the presence of antigen-specific immunoglobulins
that are derived from memory B cells or from plasma
cells could greatly facilitate the recognition and clearance of pathogens by DCs and macrophages. Whereas
the expression of activating FcγRs was once thought to
be ubiquitous on macrophages and DCs, we now realize
that cDCs and pDCs in the steady state express only low
levels of activating FcγRs, but express the inhibitory FcγR
that is involved in maintaining tolerance. It remains to
be studied whether cDCs upregulate FcγRs under conditions of inflammation and how this affects their function. Following an encounter with pathogens, monocytes
are recruited that rapidly develop into macrophages and
DCs in situ, and these cells express almost all types of
activating FcγRs. We hypothesize that the main function
of activating FcγRs on moDCs is the modification of DC
and T cell encounters at sites of inflammation, whereas
the function of FcγRs on macrophages is to promote the
clearance of pathogens in the periphery. These pathways could be exploited to boost immune responses to
tumours, and the dysregulation of FcγR function might
contribute to the development of autoimmunity.
11. Smith, K. G. & Clatworthy, M. R. FcγRIIB in autoimmunity
and infection: evolutionary and therapeutic implications.
Nature Rev. Immunol. 10, 328–343 (2010).
This paper is a particularly comprehensive review
of the biology and functions of FcγRIIB.
12. Bruhns, P. Properties of mouse and human IgG
receptors and their contribution to disease models.
Blood 119, 5640–5649 (2012).
A review that is focused on human and mouse
FcγRs, highlighting their differences and the roles
that have been attributed to them as a result of
transgenic mouse models.
13. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors: old friends
and new family members. Immunity 24, 19–28 (2006).
14.Mancardi, D. A. et al. The high-affinity human IgG
receptor FcγRI (CD64) promotes IgG-mediated
inflammation, anaphylaxis, and antitumor
immunotherapy. Blood 121, 1563–1573 (2013).
15.Mancardi, D. A. et al. FcγRIV is a mouse IgE receptor
that resembles macrophage FcεRI in humans and
promotes IgE-induced lung inflammation.
J. Clin. Invest. 118, 3738–3750 (2008).
16.Mancardi, D. A. et al. The murine high-affinity IgG
receptor FcγRIV is sufficient for autoantibody-induced
arthritis. J. Immunol. 186, 1899–1903 (2011).
17. van der Poel, C. E., Spaapen, R. M., van de
Winkel, J. G. & Leusen, J. H. Functional characteristics
of the high affinity IgG receptor, FcγRI. J. Immunol.
186, 2699–2704 (2011).
18. Li, X., Ptacek, T. S., Brown, E. E. & Edberg, J. C. Fcγ
receptors: structure, function and role as genetic risk
factors in SLE. Genes Immun. 10, 380–389 (2009).
106 | FEBRUARY 2014 | VOLUME 14
19. Nimmerjahn, F. & Ravetch, J. V. Translating basic
mechanisms of IgG effector activity into next generation
cancer therapies. Cancer Immun. 12, 13 (2012).
20. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A.
The dendritic cell lineage: ontogeny and function of
dendritic cells and their subsets in the steady state
and the inflamed setting. Annu. Rev. Immunol. 31,
563–604 (2013).
21.Schlitzer, A. et al. IRF4 transcription factor-dependent
CD11b+ dendritic cells in human and mouse control
mucosal IL‑17 cytokine responses. Immunity 38,
970–983 (2013).
22.Gatto, D. et al. The chemotactic receptor EBI2
regulates the homeostasis, localization and
immunological function of splenic dendritic cells.
Nature Immunol. 14, 446–453 (2013).
23.Plantinga, M. et al. Conventional and monocytederived CD11b+ dendritic cells initiate and maintain
T helper 2 cell-mediated immunity to house dust mite
allergen. Immunity 38, 322–335 (2013).
24. Karsten, C. M. & Kohl, J. The immunoglobulin, IgG
Fc receptor and complement triangle in autoimmune
diseases. Immunobiology 217, 1067–1079 (2012).
25.Gautier, E. L. et al. Gene-expression profiles and
transcriptional regulatory pathways that underlie the
identity and diversity of mouse tissue macrophages.
Nature Immunol. 13, 1118–1128 (2012).
This article from the Immunological Genome
Consortium identifies FcγRI and the tyrosine
protein kinase MER (MERTK) as markers that
discriminate between mouse cDCs and moDCs or
macrophages.
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
26.Miller, J. C. et al. Deciphering the transcriptional
network of the dendritic cell lineage. Nature Immunol.
13, 888–899 (2012).
27.Tamoutounour, S. et al. CD64 distinguishes
macrophages from dendritic cells in the gut and
reveals the TH1‑inducing role of mesenteric lymph node
macrophages during colitis. Eur. J. Immunol. 42,
3150–3166 (2012).
28.Flinsenberg, T. W. et al. Fcγ receptor antigen targeting
potentiates cross-presentation by human blood and
lymphoid tissue BDCA‑3+ dendritic cells. Blood 120,
5163–5172 (2012).
This article provides flow cytometry data showing
FcγR expression by distinct human immune cell
populations.
29.Robbins, S. H. et al. Novel insights into the
relationships between dendritic cell subsets in human
and mouse revealed by genome-wide expression
profiling. Genome Biol. 9, R17 (2008).
30.Haniffa, M. et al. Human tissues contain CD141hi
cross-presenting dendritic cells with functional
homology to mouse CD103+ nonlymphoid dendritic
cells. Immunity 37, 60–73 (2012).
31.Segura, E. et al. Characterization of resident and
migratory dendritic cells in human lymph nodes.
J. Exp. Med. 209, 653–660 (2012).
32.Biburger, M. et al. Monocyte subsets responsible for
immunoglobulin G‑dependent effector functions
in vivo. Immunity 35, 932–944 (2011).
33.Dobel, T. et al. FcγRIII (CD16) equips immature 6‑sulfo
LacNAc-expressing dendritic cells (slanDCs) with a
unique capacity to handle IgG-complexed antigens.
Blood 121, 3609–3618 (2013).
34.Flores, M. et al. Dominant expression of the inhibitory
FcγRIIB prevents antigen presentation by murine
plasmacytoid dendritic cells. J. Immunol. 183,
7129–7139 (2009).
This article provides flow cytometry data showing
FcγR expression by distinct mouse immune cell
populations.
35.Seeling, M. et al. Inflammatory monocytes and Fcγ
receptor IV on osteoclasts are critical for bone
destruction during inflammatory arthritis in mice.
Proc. Natl Acad. Sci. USA 110, 10729–10734 (2013).
36.Langlet, C. et al. CD64 expression distinguishes
monocyte-derived and conventional dendritic cells
and reveals their distinct role during intramuscular
immunization. J. Immunol. 188, 1751–1760 (2012).
37.Tamoutounour, S. et al. Origins and functional
specialization of macrophages and of conventional
and monocyte-derived dendritic cells in mouse skin.
Immunity 39, 925–938 (2013).
References 23, 27, 36 and 37 show the use of
FcγRI as a marker to discriminate between mouse
cDCs and moDCs and macrophages.
38. Guriec, N., Daniel, C., Le Ster, K., Hardy, E. &
Berthou, C. Cytokine-regulated expression and
inhibitory function of FcγRIIB1 and -B2 receptors in
human dendritic cells. J. Leukoc. Biol. 79, 59–70
(2006).
39.Liu, S. et al. HMGB1 is secreted by immunostimulated
enterocytes and contributes to cytomix-induced
hyperpermeability of Caco‑2 monolayers.
Am. J. Physiol. Cell Physiol. 290, C990–C999 (2006).
40. Nimmerjahn, F., Bruhns, P., Horiuchi, K. &
Ravetch, J. V. FcγRIV: a novel FcR with distinct IgG
subclass specificity. Immunity 23, 41–51 (2005).
41. te Velde, A. A., de Waal Malefijt, R., Huijbens, R. J., de
Vries, J. E. & Figdor, C. G. IL‑10 stimulates monocyte
FcγR surface expression and cytotoxic activity. Distinct
regulation of antibody-dependent cellular cytotoxicity
by IFNγ, IL‑4, and IL‑10. J. Immunol. 149, 4048–
4052 (1992).
42.Boruchov, A. M. et al. Activating and inhibitory IgG Fc
receptors on human DCs mediate opposing functions.
J. Clin. Invest. 115, 2914–2923 (2005).
43.Segura, E. et al. Human inflammatory dendritic cells
induce TH17 cell differentiation. Immunity 38, 336–
348 (2013).
This article shows the use of FcεRI as a marker to
discriminate between human cDCs and moDCs.
44.Means, T. K. et al. Human lupus autoantibody–DNA
complexes activate DCs through cooperation of CD32
and TLR9. J. Clin. Invest. 115, 407–417 (2005).
45. Amigorena, S., Salamero, J., Davoust, J., Fridman, W. H.
& Bonnerot, C. Tyrosine-containing motif that
transduces cell activation signals also determines
internalization and antigen presentation via type III
receptors for IgG. Nature 358, 337–341 (1992).
46. Miettinen, H. M., Rose, J. K. & Mellman, I. Fc receptor
isoforms exhibit distinct abilities for coated pit
localization as a result of cytoplasmic domain
heterogeneity. Cell 58, 317–327 (1989).
47. Amigorena, S. & Bonnerot, C. Fc receptor signaling
and trafficking: a connection for antigen processing.
Immunol. Rev. 172, 279–284 (1999).
48. Bergtold, A., Desai, D. D., Gavhane, A. & Clynes, R.
Cell surface recycling of internalized antigen permits
dendritic cell priming of B cells. Immunity 23,
503–514 (2005).
49.Hoffmann, E. et al. Autonomous phagosomal
degradation and antigen presentation in dendritic cells.
Proc. Natl Acad. Sci. USA 109, 14556–14561 (2012).
This report shows that IgG-mediated opsonization
enhances antigen presentation to CD4+ T cells only
when antigens and IgG are present within the same
phagosome.
50.Qiao, S. W. et al. Dependence of antibody-mediated
presentation of antigen on FcRn. Proc. Natl Acad. Sci.
USA 105, 9337–9342 (2008).
51.Baker, K. et al. Neonatal Fc receptor for IgG (FcRn)
regulates cross-presentation of IgG immune
complexes by CD8‑CD11b+ dendritic cells.
Proc. Natl Acad. Sci. USA 108, 9927–9932 (2011).
References 50 and 51 show the role of FcRn in
antigen presentation by DCs when antigens are
opsonized by IgG.
52.Zhu, X. et al. MHC class I‑related neonatal Fc receptor
for IgG is functionally expressed in monocytes,
intestinal macrophages, and dendritic cells.
J. Immunol. 166, 3266–3276 (2001).
53.Vidarsson, G. et al. FcRn: an IgG receptor on
phagocytes with a novel role in phagocytosis.
Blood 108, 3573–3579 (2006).
54.McEwan, W. A. et al. Intracellular antibody-bound
pathogens stimulate immune signaling via the Fc
receptor TRIM21. Nature Immunol. 14, 327–336
(2013).
References 5 and 54 describe TRIM21 as an
intracellular IgG receptor.
55. McEwan, W. A., Mallery, D. L., Rhodes, D. A.,
Trowsdale, J. & James, L. C. Intracellular antibodymediated immunity and the role of TRIM21.
Bioessays 33, 803–809 (2011).
56.Bonnerot, C. et al. Syk protein tyrosine kinase
regulates Fc receptor γ-chain-mediated transport to
lysosomes. EMBO J. 17, 4606–4616 (1998).
57. Odin, J. A., Edberg, J. C., Painter, C. J., Kimberly, R. P.
& Unkeless, J. C. Regulation of phagocytosis and
[Ca2+]i flux by distinct regions of an Fc receptor.
Science 254, 1785–1788 (1991).
58.Edberg, J. C. et al. The cytoplasmic domain of human
FcγRIa alters the functional properties of the FcγRI
γ-chain receptor complex. J. Biol. Chem. 274,
30328–30333 (1999).
59. Li, F. & Ravetch, J. V. A general requirement for
FcγRIIB co‑engagement of agonistic anti-TNFR
antibodies. Cell Cycle 11, 3343–3344 (2012).
60. Hernandez, M., Fuentes, L., Fernandez Aviles, F. J.,
Crespo, M. S. & Nieto, M. L. Secretory phospholipase
A2 elicits proinflammatory changes and upregulates
the surface expression of fas ligand in monocytic cells:
potential relevance for atherogenesis. Circul. Res. 90,
38–45 (2002).
61.Dhodapkar, K. M. et al. Selective blockade of the
inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells
and monocytes induces a type I interferon response
program. J. Exp. Med. 204, 1359–1369 (2007).
62. Sutterwala, F. S., Noel, G. J., Clynes, R. &
Mosser, D. M. Selective suppression of interleukin‑12
induction after macrophage receptor ligation.
J. Exp. Med. 185, 1977–1985 (1997).
This article describes the alternative activation
state of macrophages following FcγR triggering.
63. Mosser, D. M. & Edwards, J. P. Exploring the full
spectrum of macrophage activation. Nature Rev.
Immunol. 8, 958–969 (2008).
64.Mantovani, A. et al. The chemokine system in diverse
forms of macrophage activation and polarization.
Trends Immunol. 25, 677–686 (2004).
65.Clynes, R. et al. Modulation of immune complexinduced inflammation in vivo by the coordinate
expression of activation and inhibitory Fc receptors.
J. Exp. Med. 189, 179–185 (1999).
66.Yuasa, T. et al. Deletion of fcγ receptor IIB renders
H-2b mice susceptible to collagen-induced arthritis.
J. Exp. Med. 189, 187–194 (1999).
67. Clatworthy, M. R. & Smith, K. G. FcγRIIb balances
efficient pathogen clearance and the cytokinemediated consequences of sepsis. J. Exp. Med. 199,
717–723 (2004).
68.Brownlie, R. J. et al. Distinct cell-specific control of
autoimmunity and infection by FcγRIIb. J. Exp. Med.
205, 883–895 (2008).
References 65–68 show that the balance between
activating ITAM-bearing FcγRs and the inhibitory
NATURE REVIEWS | IMMUNOLOGY
ITIM-bearing FcγRIIB controls the threshold for cell
activation.
69. Hubber, A. & Roy, C. R. Modulation of host cell
function by Legionella pneumophila type IV effectors.
Annu. Rev. Cell Dev. Biol. 26, 261–283 (2010).
70. Hunter, C. A. & Sibley, L. D. Modulation of innate
immunity by Toxoplasma gondii virulence effectors.
Nature Rev. Microbiol. 10, 766–778 (2012).
71.Joller, N. et al. Antibodies protect against intracellular
bacteria by Fc receptor-mediated lysosomal targeting.
Proc. Natl Acad. Sci. USA 107, 20441–20446 (2010).
72. Maglione, P. J., Xu, J., Casadevall, A. & Chan, J. Fcγ
receptors regulate immune activation and
susceptibility during Mycobacterium tuberculosis
infection. J. Immunol. 180, 3329–3338 (2008).
73. Joller, N., Weber, S. S. & Oxenius, A. Antibody‑Fc
receptor interactions in protection against
intracellular pathogens. Eur. J. Immunol. 41,
889–897 (2011).
74.Yona, S. et al. Fate mapping reveals origins and
dynamics of monocytes and tissue macrophages
under homeostasis. Immunity 38, 79–91 (2013).
75.Schulz, C. et al. A lineage of myeloid cells independent
of Myb and hematopoietic stem cells. Science 336,
86–90 (2012).
76.Hashimoto, D. et al. Tissue-resident macrophages
self-maintain locally throughout adult life with
minimal contribution from circulating monocytes.
Immunity 38, 792–804 (2013).
77.Guilliams, M. et al. Alveolar macrophages develop
from fetal monocytes that differentiate into long-lived
cells in the first week of life via GM‑CSF. J. Exp. Med.
210, 1977–1992 (2013).
78. Halstead, S. B., Mahalingam, S., Marovich, M. A.,
Ubol, S. & Mosser, D. M. Intrinsic antibody-dependent
enhancement of microbial infection in macrophages:
disease regulation by immune complexes. Lancet
Infect. Dis. 10, 712–722 (2010).
79. Guzman, M. G. & Vazquez, S. The complexity of
antibody-dependent enhancement of dengue virus
infection. Viruses 2, 2649–2662 (2010).
80. Kliks, S. C., Nimmanitya, S., Nisalak, A. & Burke, D. S.
Evidence that maternal dengue antibodies are
important in the development of dengue hemorrhagic
fever in infants. Am. J. Trop. Med. Hyg. 38, 411–419
(1988).
81.Gonzalez, D. et al. Classical dengue hemorrhagic
fever resulting from two dengue infections spaced
20 years or more apart: Havana, Dengue 3 epidemic,
2001–2002. Int. J. Infect. Dis. 9, 280–285 (2005).
82. Denkers, E. Y. & Butcher, B. A. Sabotage and
exploitation in macrophages parasitized by
intracellular protozoans. Trends Parasitol. 21, 35–41
(2005).
83. Yang, Z., Mosser, D. M. & Zhang, X. Activation of the
MAPK, ERK, following Leishmania amazonensis
infection of macrophages. J. Immunol. 178,
1077–1085 (2007).
84. Padigel, U. M. & Farrell, J. P. Control of infection with
Leishmania major in susceptible BALB/c mice lacking
the common γ-chain for FcR is associated with reduced
production of IL‑10 and TGF-β by parasitized cells.
J. Immunol. 174, 6340–6345 (2005).
85.Kima, P. E. et al. Internalization of Leishmania
mexicana complex amastigotes via the Fc receptor is
required to sustain infection in murine cutaneous
leishmaniasis. J. Exp. Med. 191, 1063–1068 (2000).
86. Miles, S. A., Conrad, S. M., Alves, R. G.,
Jeronimo, S. M. & Mosser, D. M. A role for IgG
immune complexes during infection with the
intracellular pathogen Leishmania. J. Exp. Med.
201, 747–754 (2005).
87.Regnault, A. et al. Fcγ receptor-mediated induction of
dendritic cell maturation and major histocompatibility
complex class I‑restricted antigen presentation after
immune complex internalization. J. Exp. Med.
189, 371–380 (1999).
88.Heijnen, I. A. et al. Antigen targeting to myeloidspecific human FcγRI/CD64 triggers enhanced
antibody responses in transgenic mice. J. Clin. Invest.
97, 331–338 (1996).
References 45, 87 and 88 show that FcγR
triggering improves presentation of an antigen
that is contained in an immune complex.
89. den Haan, J. M. & Bevan, M. J. Constitutive versus
activation-dependent cross-presentation of immune
complexes by CD8+ and CD8– dendritic cells in vivo.
J. Exp. Med. 196, 817–827 (2002).
90. Tobar, J. A., Gonzalez, P. A. & Kalergis, A. M.
Salmonella escape from antigen presentation can be
overcome by targeting bacteria to Fcγ receptors on
dendritic cells. J. Immunol. 173, 4058–4065
(2004).
VOLUME 14 | FEBRUARY 2014 | 107
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
91.Akiyama, K. et al. Targeting apoptotic tumor cells to
FcγR provides efficient and versatile vaccination
against tumors by dendritic cells. J. Immunol. 170,
1641–1648 (2003).
92. Celis, E. & Chang, T. W. Antibodies to hepatitis B
surface antigen potentiate the response of human T
lymphocyte clones to the same antigen. Science 224,
297–299 (1984).
93. van Montfoort, N. et al. Fcγ receptor IIb strongly
regulates Fcγ receptor-facilitated T cell activation by
dendritic cells. J. Immunol. 189, 92–101 (2012).
94.Schuurhuis, D. H. et al. Antigen-antibody immune
complexes empower dendritic cells to efficiently prime
specific CD8+ CTL responses in vivo. J. Immunol. 168,
2240–2246 (2002).
95. Rafiq, K., Bergtold, A. & Clynes, R. Immune complexmediated antigen presentation induces tumor
immunity. J. Clin. Invest. 110, 71–79 (2002).
96.Desai, D. D. et al. Fcγ receptor IIB on dendritic cells
enforces peripheral tolerance by inhibiting effector
T cell responses. J. Immunol. 178, 6217–6226 (2007).
97.Yada, A. et al. Accelerated antigen presentation and
elicitation of humoral response in vivo by FcγRIIBand FcγRI/III-mediated immune complex uptake.
Cell. Immunol. 225, 21–32 (2003).
References 89, 93 and 97 show that antigens
associated with immunoglobulins are more
efficiently cross-presented by DCs.
98. de Jong, J. M. et al. Murine Fc receptors for IgG are
redundant in facilitating presentation of immune
complex derived antigen to CD8+ T cells in vivo.
Mol. Immunol. 43, 2045–2050 (2006).
99.Ioan-Facsinay, A. et al. FcγRI (CD64) contributes
substantially to severity of arthritis, hypersensitivity
responses, and protection from bacterial infection.
Immunity 16, 391–402 (2002).
Together with reference 14, this paper
demonstrates the contribution of FcγRI to
IgG-mediated immune response in vivo.
100.Dhodapkar, K. M. et al. Selective blockade of
inhibitory Fcγ receptor enables human dendritic cell
maturation with IL‑12p70 production and immunity to
antibody-coated tumor cells. Proc. Natl Acad. Sci. USA
102, 2910–2915 (2005).
101.Liu, Y. et al. Regulated expression of FcγR in human
dendritic cells controls cross-presentation of antigenantibody complexes. J. Immunol. 177, 8440–8447
(2006).
102.Dai, X. et al. Differential signal transduction, membrane
trafficking, and immune effector functions mediated by
FcγRI versus FcγRIIa. Blood 114, 318–327 (2009).
This study shows that even if two different FcγRs
are associated with the same signalling subunit
(that is, the FcR γ‑chain), their downstream
signalling is dissimilar and leads to different
cellular responses.
103.Persson, E. K. et al. IRF4 transcription-factor-dependent
CD103+CD11b+ dendritic cells drive mucosal T helper
17 cell differentiation. Immunity 38, 958–969 (2013).
104.McLachlan, J. B., Catron, D. M., Moon, J. J. &
Jenkins, M. K. Dendritic cell antigen presentation
drives simultaneous cytokine production by effector
and regulatory T cells in inflamed skin. Immunity 30,
277–288 (2009).
105.Iijima, N., Mattei, L. M. & Iwasaki, A. Recruited
inflammatory monocytes stimulate antiviral TH1
immunity in infected tissue. Proc. Natl Acad. Sci. USA
108, 284–289 (2011).
106.Woelbing, F. et al. Uptake of Leishmania major by
dendritic cells is mediated by Fcγ receptors and
facilitates acquisition of protective immunity. J. Exp.
Med. 203, 177–188 (2006).
107. Bjorck, P., Beilhack, A., Herman, E. I., Negrin, R. S. &
Engleman, E. G. Plasmacytoid dendritic cells take up
opsonized antigen leading to CD4+ and CD8+ T cell
activation in vivo. J. Immunol. 181, 3811–3817 (2008).
108.Bandukwala, H. S. et al. Signaling through FcγRIII is
required for optimal T helper type (TH)2 responses and
TH2‑mediated airway inflammation. J. Exp. Med. 204,
1875–1889 (2007).
109.Kitamura, K. et al. Critical role of the Fc receptor
γ-chain on APCs in the development of allergeninduced airway hyperresponsiveness and
inflammation. J. Immunol. 178, 480–488 (2007).
References 61, 93, 95, 106, 108 and 109
collectively show that FcγR triggering induces DC
maturation and increases their capacity to induce
the differentiation of effector T cells (that is, TH1
or TH2 cells, depending on the model).
110.Hartwig, C. et al. Fcγ receptor-mediated antigen uptake
by lung DC contributes to allergic airway hyperresponsiveness and inflammation. Eur. J. Immunol. 40,
1284–1295 (2010).
111.Tjota, M. Y. et al. IL‑33‑dependent induction of allergic
lung inflammation by FcγRIII signaling. J. Clin. Invest.
123, 2287–2297 (2013).
112. Blink, S. E. & Fu, Y. X. IgE regulates T helper cell
differentiation through FcγRIII mediated dendritic cell
cytokine modulation. Cell. Immunol. 264, 54–60 (2010).
113. Kalergis, A. M. & Ravetch, J. V. Inducing tumor
immunity through the selective engagement of
activating Fcγ receptors on dendritic cells. J. Exp.
Med. 195, 1653–1659 (2002).
114. McGaha, T. L., Karlsson, M. C. & Ravetch, J. V.
FcγRIIB deficiency leads to autoimmunity and a
defective response to apoptosis in Mrl-MpJ mice.
J. Immunol. 180, 5670–5679 (2008).
115.Samsom, J. N. et al. FcγRIIB regulates nasal and oral
tolerance: a role for dendritic cells. J. Immunol. 174,
5279–5287 (2005).
116.Wenink, M. H. et al. The inhibitory FcγIIb receptor
dampens TLR4‑mediated immune responses and is
selectively up‑regulated on dendritic cells from
rheumatoid arthritis patients with quiescent disease.
J. Immunol. 183, 4509–4520 (2009).
117.Laborde, E. A. et al. Immune complexes inhibit
differentiation, maturation, and function of human
monocyte-derived dendritic cells. J. Immunol. 179,
673–681 (2007).
118.Tridandapani, S. et al. Regulated expression and
inhibitory function of FcγRIIb in human monocytic
cells. J. Biol. Chem. 277, 5082–5089 (2002).
119.Tridandapani, S. et al. TGF‑β1 suppresses [correction of
supresses] myeloid Fcγ receptor function by regulating
the expression and function of the common γ-subunit.
J. Immunol. 170, 4572–4577 (2003).
120.Pricop, L. et al. Differential modulation of stimulatory
and inhibitory Fcγ receptors on human monocytes by
TH1 and TH2 cytokines. J. Immunol. 166, 531–537
(2001).
121.Sallusto, F. & Lanzavecchia, A. Efficient presentation
of soluble antigen by cultured human dendritic cells
is maintained by granulocyte/macrophage colonystimulating factor plus interleukin‑4 and
downregulated by tumor necrosis factor-α.
J. Exp. Med. 179, 1109–1118 (1994).
122.Tel, J. et al. Human plasmacytoid dendritic cells
efficiently cross-present exogenous Ags to CD8+
T cells despite lower Ag uptake than myeloid dendritic
cell subsets. Blood 121, 459–467 (2013).
123.Benitez-Ribas, D. et al. Plasmacytoid dendritic cells
of melanoma patients present exogenous proteins
to CD4+ T cells after FcγRII-mediated uptake.
J. Exp. Med. 203, 1629–1635 (2006).
124.Benitez-Ribas, D., Tacken, P., Punt, C. J., de Vries, I. J.
& Figdor, C. G. Activation of human plasmacytoid
dendritic cells by TLR9 impairs FcγRII-mediated
uptake of immune complexes and presentation by
MHC class II. J. Immunol. 181, 5219–5224 (2008).
125.Kool, M. et al. Facilitated antigen uptake and timed
exposure to TLR ligands dictate the antigen-presenting
potential of plasmacytoid DCs. J. Leukoc. Biol. 90,
1177–1190 (2011).
References 123, 124 and 125 show that triggering
of FcγRs endows pDCs with the capacity to
efficiently present antigens to T cells.
126.Gilliet, M., Cao, W. & Liu, Y. J. Plasmacytoid dendritic
cells: sensing nucleic acids in viral infection and
autoimmune diseases. Nature Rev. Immunol. 8,
594–606 (2008).
127.Tian, J. et al. Toll-like receptor 9‑dependent activation
by DNA-containing immune complexes is mediated
by HMGB1 and RAGE. Nature Immunol. 8, 487–496
(2007).
128.Henault, J. et al. Noncanonical autophagy is required
for type I interferon secretion in response to DNAimmune complexes. Immunity 37, 986–997 (2012).
DNA-containing immune complexes induce type I
IFN secretion by pDCs through a convergence of
the phagocytic and the non-canonical autophagic
pathway.
129.Parcina, M. et al. Staphylococcus aureus-induced
plasmacytoid dendritic cell activation is based on an
IgG-mediated memory response. J. Immunol. 181,
3823–3833 (2008).
130.Tel, J. et al. Targeted delivery of CpG ODN to CD32
on human and monkey plasmacytoid dendritic cells
augments IFNα secretion. Immunobiology 217,
1017–1024 (2012).
131.Boule, M. W. et al. Toll-like receptor 9‑dependent and
-independent dendritic cell activation by chromatinimmunoglobulin G complexes. J. Exp. Med. 199,
1631–1640 (2004).
132.Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V.
Inhibitory Fc receptors modulate in vivo cytotoxicity
against tumor targets. Nature Med. 6, 443–446 (2000).
108 | FEBRUARY 2014 | VOLUME 14
133.Schwab, I. & Nimmerjahn, F. Intravenous
immunoglobulin therapy: how does IgG modulate the
immune system? Nature Rev. Immunol. 13, 176–189
(2013).
134.Kaneko, Y., Nimmerjahn, F., Madaio, M. P. &
Ravetch, J. V. Pathology and protection in nephrotoxic
nephritis is determined by selective engagement of
specific Fc receptors. J. Exp. Med. 203, 789–797
(2006).
135.Samuelsson, A., Towers, T. L. & Ravetch, J. V. Antiinflammatory activity of IVIG mediated through the
inhibitory Fc receptor. Science 291, 484–486
(2001).
136.Crow, A. R. et al. IVIg-mediated amelioration of murine
ITP via FcγRIIB is independent of SHIP1, SHP‑1, and
Btk activity. Blood 102, 558–560 (2003).
137.Bruhns, P., Samuelsson, A., Pollard, J. W. &
Ravetch, J. V. Colony-stimulating factor‑1‑dependent
macrophages are responsible for IVIG protection in
antibody-induced autoimmune disease. Immunity 18,
573–581 (2003).
138.Siragam, V. et al. Intravenous immunoglobulin
ameliorates ITP via activating Fcγ receptors on
dendritic cells. Nature Med. 12, 688–692 (2006).
139.Bayry, J. et al. Inhibition of maturation and function
of dendritic cells by intravenous immunoglobulin.
Blood 101, 758–765 (2003).
140.Anthony, R. M., Kobayashi, T., Wermeling, F. &
Ravetch, J. V. Intravenous gammaglobulin suppresses
inflammation through a novel TH2 pathway. Nature
475, 110–113 (2011).
141.Akilesh, S. et al. The MHC class I‑like Fc receptor
promotes humorally mediated autoimmune disease.
J. Clin. Invest. 113, 1328–1333 (2004).
142.Serbina, N. V. & Pamer, E. G. Monocyte emigration
from bone marrow during bacterial infection requires
signals mediated by chemokine receptor CCR2.
Nature Immunol. 7, 311–317 (2006).
143.Grayson, M. H. et al. Induction of high-affinity IgE
receptor on lung dendritic cells during viral infection
leads to mucous cell metaplasia. J. Exp. Med. 204,
2759–2769 (2007).
144.Hammad, H. et al. Inflammatory dendritic cells — not
basophils — are necessary and sufficient for induction
of TH2 immunity to inhaled house dust mite allergen.
J. Exp. Med. 207, 2097–2111 (2010).
References 23, 143 and144 show the power of
using FcγRI and FcεRI as markers to discriminate
between mouse cDCs and moDCs.
145.Painter, M. W., Davis, S., Hardy, R. R., Mathis, D. &
Benoist, C. Transcriptomes of the B and T lineages
compared by multiplatform microarray profiling.
J. Immunol. 186, 3047–3057 (2011).
146.Stetson, D. B. & Medzhitov, R. Recognition of cytosolic
DNA activates an IRF3‑dependent innate immune
response. Immunity 24, 93–103 (2006).
147.Zigmond, E. et al. Ly6Chi monocytes in the inflamed
colon give rise to proinflammatory effector cells and
migratory antigen-presenting cells. Immunity 37,
1076–1090 (2012).
148.Lee, S. M. et al. Systems-level comparison of hostresponses elicited by avian H5N1 and seasonal H1N1
influenza viruses in primary human macrophages.
PLoS ONE 4, e8072 (2009).
149.Braun, D. A., Fribourg, M. & Sealfon, S. C. Cytokine
response is determined by duration of receptor and
signal transducers and activators of transcription 3
(STAT3) activation. J. Biol. Chem. 288, 2986–2993
(2013).
150.Martinez, F. O. et al. Genetic programs expressed in
resting and IL‑4 alternatively activated mouse and
human macrophages: similarities and differences.
Blood 121, e57–e69 (2013).
151.Saylor, C. A., Dadachova, E. & Casadevall, A.
Murine IgG1 and IgG3 isotype switch variants
promote phagocytosis of Cryptococcus neoformans
through different receptors. J. Immunol. 184,
336–343 (2010).
152.Steinman, R. M. & Cohn, Z. A. Identification of a novel
cell type in peripheral organs in mice. II. Functional
properties in vitro. 139, 380–397 (1974).
Competing interests statement
The authors declare no competing interests.
FURTHER INFORMATION
Immunological Genome Consortium: http://www.immgen.org/
SUPPLEMENTARY INFORMATION
See online article: S1 (figure)
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
www.nature.com/reviews/immunol
© 2014 Macmillan Publishers Limited. All rights reserved
ERRATUM
The function of Fcγ receptors in dendritic cells and macrophages
Martin Guilliams, Pierre Bruhns, Yvan Saeys, Hamida Hammad and Bart N. Lambrecht
Nature Reviews Immunology 14, 94–108 (2014)
In the version of this Review that was initially published, the images in Table 2 showing the structure of FcγRIIB and FcγRIII
were in the wrong order. This error has been corrected in the online HTML and PDF versions of the article. Nature Reviews
Immunology apologizes for this error.
© 2014 Macmillan Publishers Limited. All rights reserved