International Immunology, Vol. 23, No. 8, pp. 467–472 ª The Japanese Society for Immunology. 2011.

unology. 2011. All rights reserved.

doi:10.1093/intimm/dxr046 For permissions, please e-mail: journals.permissions@oup.com
Advance Access publication 15 June 2011

Dectin-1 and Dectin-2 in innate immunity against

fungi
Shinobu Saijo1,2 and Yoichiro Iwakura3,4
1
Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan
2
PRESTO, Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
3
Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical
Science, The University of Tokyo, Tokyo108-8639, Japan
4

REVIEW
Downloaded from https://academic.oup.com/intimm/article/23/8/467/673118 by guest on 17 October 2020
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama
332-0012, Japan

Correspondence to: Y. Iwakura; E-mail: iwakura@ims.u-tokyo.ac.jp

Received 11 March 2011, accepted 30 May 2011

Abstract
Dectin-1 and Dectin-2 are type II transmembrane proteins of the C-type lectin family with single
carbohydrate recognition domains (CRDs) in their extracellular region. They are expressed mainly in
dendritic cells and macrophages. Dectin-1 recognizes b-glucans with its CRD and transduces signals
through its immunoreceptor tyrosine-based activation motif (ITAM)-like motif in the cytoplasmic
domain, whereas Dectin-2 recognizes a-mannans and transduces its signal through association with
the ITAM-containing Fc receptor g chain. Upon ligand binding, spleen tyrosine kinase is recruited to
the ITAM and activates the caspase recruitment domain family member 9 (CARD9)–nuclear factor-kB
axis, resulting in the activation of various genes including those encoding pro-inflammatory
cytokines. Both b-glucans and a-mannans are major cell wall components of fungi including Candida
albicans and Pneumocystis carinii. Recently, it was reported that Dectin-1 is important in protection
against P. carinii by inducing reactive oxygen species, whereas both Dectin-1 and Dectin-2 play
important roles in defense against C. albicans by preferentially inducing Th17 cell differentiation. In
this review, we briefly revisit the structures, ligands, signal transduction and functional roles of
Dectin-1 and Dectin-2 in host defense against fungal infection.

Keywords: cytokine, Dectin-1, Dectin-2, innate immunity, Th17

Introduction
The C-type lectins are one of the pattern recognition recep-
tors (PRRs) with lectin-like carbohydrate recognition domains
(CRDs) in their extracellular carboxy-terminal domains (1, 2).
Some C-type lectin family members recognize the carbohy-
drate structures of microbes as pathogen-associated
molecular patterns (PAMPs), whereas some members on NK
cells recognize endogenous ligands and discriminate self
from non-self. Similar to other PRRs such as Toll-like recep-
tors (TLRs), C-type lectins that recognize PAMPs are also in-
volved in host defense mechanisms against infection (3).
However, different from TLRs, which recognize various
PAMPs such as lipopolysaccharides, proteoglycans, DNAs
and RNAs, C-type lectins mostly recognize carbohydrate
structures in pathogens.
Fungal cell walls are mainly composed of multiple layers of
carbohydrates, including mannans (polymers of mannose),
b-glucans (polymers of D-glucose linked by b-glycosidic
bonds) and chitins (polymers of N-acetyl-D-glucosamine).
These cell wall components are thought to be recognized by
C-type lectins including macrophage mannose receptor
(MR, CD206, Mrc1), SIGNR-1 (CD209, human DC-SIGN),
Galectin-3, Mincle, Dectin-1 and Dectin-2 to activate host in-
nate immune system. MR recognizes the terminal a-(1,2)/
(1,3)-mannose of N-linked mannans of fungal cell walls, while
SIGNR-1 recognizes branched a-mannans and Galectin-3
recognizes b-(1, 2)-mannans (4–6). However, MR-deficient
mice show normal host defense during systemic candidiasis
and macrophages isolated from MR-deficient mice show nor-
mal susceptibility to Candida albicans infection (7), although
this receptor is suggested to be involved in host defense
against C. albicans in humans through induction of Th17 cell
differentiation (8, 9). Macrophages from Galectin-3-deficient
mice show normal binding and endocytosis of C. albicans
(10). Whether SIGNR-1-deficient mice are sensitive to
Candida infection has not been reported yet. Mincle recog-
nizes a-mannose structure and is suggested to be involved
468 Dectin-1 and Dectin-2 in innate immunity
in the host defense against Malassezia, although this receptor
is not involved in C. albicans eradication (11). Recently, we
and others reported that Dectin-1 (gene symbol Clec7a) and
Dectin-2 (Clec4n) are the specific receptors for b-glucans
(12, 13) and C. albicans-derived a-mannans (14), respec-
tively, and induce cytokines and reactive oxygen species
(ROS) to protect hosts from fungal infection through activation
of the spleen tyrosine kinase (Syk)–caspase recruitment do-
main family member 9 (CARD9)–nuclear factor-jB (NF-jB)
pathway in dendritic cells (DCs) and macrophages (3). In this
review, we will briefly summarize recent research progress in
Dectin-1 and Dectin-2, the most well-studied C-type lectins
especially in response to fungal infection.
The structure of Dectin-1 and Dectin-2
Dectin-1 and Decin-2 are members of the C-type lectin family,
whose genes are located in the telomeric region of the mouse
chromosome 6 and human chromosome 12q, where many
C-type lectin genes are located and form several clusters. Both
Dectin-1 and Dectin-2 are glycosylated type II transmembrane
proteins with single CRDs, which are highly conserved in mice
and humans (amino acid identities: Dectin-1 63% and Dectin-2
75%). Whereas Dectin-1 has a tyrosine-based activation motif
(ITAM)-like motif (hemITAM) in its intracellular region, Dectin-2
has no known signaling motif in its shorter cytoplasmic region.
These structures are shared by mice and humans.
Dectin-1 was originally identified as a DC-specific C-type
lectin by subtraction array with the XS52 DC cell line (15). Ex-
pression was also detected in macrophages and neutrophils
(16). Initially, it was reported that T cells express an unknown
Dectin-1 ligand, which induces T-cell proliferation upon Dec-
tin-1 binding (15), although this needs to be confirmed. More
importantly, Dectin-1 binds to b-glucans in a Ca2+-independent
fashion differently from most other C-type lectins (17).
Dectin-2 was originally identified as Langerhans cell-
specific C-type lectin using the murine Langerhans cell-like
cell line XS52, and its expression is also detected in DCs
and macrophages (18, 19). This molecule has a CRD con-
taining an EPN (Glu–Pro–Asn) motif, a Ca2+-dependent
mannose-binding amino acid sequence, and binds ‘high
mannose’-type carbohydrates (i.e. with high mannose con-
tent) as well as C. albicans hyphae (20). Dectin-2 lacks
a known signaling motif in the cytoplasmic domain.
Because Dectin-2 have no arginine in its transmembrane re-
gion which is important for membrane association with ITAM-
containing signaling molecules such as Fc receptor c (FcRc)
chain or DNAX-activating protein of 12 kDa (DAP12), the sig-
naling mechanism remained unknown for a while. However, it
was shown that Dectin-2 associates with FcRc chain via the
arginine residue in the cytoplasmic domain of Dectin-2 (20).
The FcRc chain is required for the biological function of Dec-
tin-2 because cytokine production was abolished in FcRc
chain-deficient mice despite a-mannan stimulation (14).
The ligands for Dectin-1 and Dectin-2
b-Glucans are an important cell wall component of fungi;
the backbone structure consists of polymerized b-1,
3-linked b-D-glucopyranosyl units with b-1 and 6-linked side
chains. b-Glucans are found in a wide range of edible
mushrooms, seaweeds, yeasts and pathogenic fungi in-
cluding C. albicans and Pneumocystis carinii, and various
chain lengths and branchings are characteristics of each
fungal species (21). It is widely accepted that b-glucans
are located in the inner layer between the mannan and chitin
layers as skeletal components of the candida cell wall, and
they are exposed on the cell surface at budding sites (6).
Cytokine [e.g. tumor necrosis factor (TNF) and IL-12]
production occurred in bone marrow-derived DCs (BMDCs)
stimulated with b-glucans purified from edible mushroom
(Sparassis crispa glucan) or in macrophages treated with
NaClO-oxydized zymosan, in which proteoglycans were
disrupted; such production was completely abolished when
BMDCs or macrophages were prepared from Dectin-1-defi-
Downloaded from https://academic.oup.com/intimm/article/23/8/467/673118 by guest on 17 October 2020
cient mice, indicating that Dectin-1 is the functional recep-
tor for b-glucans (14). Dectin-1-deficient macrophages also
could not bind purified b-glucans from C. albicans. Interest-
ingly, Dectin-1-deficient peritoneal macrophages showed
normal binding to live C. albicans, suggesting that other
receptors than Dectin-1 are used for the binding receptors
in live fungi (14). Consistent with this, cytokine production
induced by C. albicans or zymosan is not dependent on
Dectin-1 but on myeloid differentiation primary response
gene 88 (MyD88), suggesting that TLRs are mainly in-
volved in these responses. Taylor et al. (12), however,
showed that Dectin-1-deficient cells cannot bind live C.
albicans using another fungal strain. Thus, b-glucan pre-
sentation on the cell wall may differ among fungal strains.
Using glycan arrays (in which glycans are coated onto sub-
strates to investigate what they bind), it was shown that Dec-
tin-2 binds high-mannose structures that are distributed in
a wide range of species including fungi (20, 22). Recent stud-
ies using Dectin-2-deficient mice have clearly shown that
Dectin-2 is the functional receptor for a-mannans because cy-
tokine production was completely abolished in BMDCs from
Dectin-2-deficient mice upon treatment with C. albicans cell
wall a-mannans (14). Mannans from Serotype A C. albicans
consist of a-1, 6-linked polymannoses attached to Asn resi-
dues with a-1, 2-linked mannose side chains. Mannans from
C. albicans also have b-1, 2-linked mannose residues at-
tached to its a-1, 2-linked oligomannose side chains (23, 24).
However, b-mannan is not involved in the Dectin-2 recognition
of candida mannans because cell wall mannans from which
b-mannans were eliminated could induce cytokines in BMDCs
as efficiently as natural candida mannans and this cytokine
production disappeared in Dectin-2-deficient DCs (14).
Dectin-1 and Dectin-2 signaling
Dectin-1 has an ITAM-like domain in its cytoplasmic part. Al-
though it was well known that phosphorylation of ITAM recruits
tandem Src-homology 2 (SH2) domain-containing tyrosine
kinases such as f-chain-associated protein kinase 70 kDa
(ZAP-70) in T cells and Syk in B cells, it had not been known
until recently how ITAM-containing receptors in myeloid cells
transduce their signaling. Rogers et al. (25) showed that Syk
is recruited to the ITAM of Dectin-1, and phosphorylated Syk
is accumulated at the phagocytosis cup during internalization
of zymosan. Dectin-1-dependent cytokine production,
mitogen-activated protein kinase (MAPK) activation and NF-jB

activation are inhibited by Syk deficiency or Syk inhibitors, sug-
gesting that Syk is involved in signal transduction. Furthermore,
Syk is also involved in Dectin-2 signal transduction: Syk and
MAPK phosphorylation were induced by the treatment of
BMDCs with Dectin-2 mAb or a-mannans, and the production
of cytokines such as IL-2, IL-10 and TNF was not found in
Syk-deficient BMDCs (14, 26) (Fig. 1).
CARD9 has a coiled-coil region at the C-terminus and
a CARD domain in the N-terminus. The CARD of CARD9 di-
rectly binds the CARD of B-cell lymphoma 10 (BCL10)
through CARD–CARD interaction (27). The use of CARD9-
deficient mice revealed that this protein is essential for cyto-
kine production induced by Dectin-1 and Dectin-2 (14, 28).
Because cytokine production was also not found in BCL10-
Dectin-1 and Dectin-2 in innate immunity 469
were activated with Dectin-1 or Dectin-2 stimulation, CARD9
deficiency caused a defect only in the NF-jB pathway, but
not in the MAPK pathway, resulting in the lack of cytokine
production. Thus, the Syk–(CARD9–BCL10–MALT1)–NF-jB
pathway is crucial for the cytokine induction by these C-type
lectins, and the MAPK pathway is not involved in the induction
(14, 28, 29).
Dectin-1 activates not only canonical NF-jB subunits p65
(RelA) and c-Rel in a Syk-dependent manner but also acti-
vates non-canonical NF-jB subunit RelB, which suppresses
Th1 and Th17 differentiation (30). This RelB activation is
antagonized by Raf-1, which is also activated by Dectin-1
signaling in a Syk-independent manner, by enhancing inac-
tive p65–RelB dimer formation via inducing phosphorylation

Downloaded from https://academic.oup.com/intimm/article/23/8/467/673118 by guest on 17 October 2020

deficient cells and mucosa-associated lymphoid tissue lym-
phoma translocation gene 1 (MALT1)-deficient BMDCs, it
was suggested that CARD9 forms a trimolecular complex in
myeloid cells like the CARD11–BCL10–MALT1 complex in
lymphocytes.
CARD9-deficient mice are more susceptible to candida in-
fection, and cytokine production almost completely disappears
in CARD9-deficient BMDCs upon treatment with the yeast form
or the hyphal form of C. albicans, suggesting that cytokine
production is important for protection against fungal infection
(14). Although both the MAPK pathway and NF-jB pathway
of p65. Thus, Dectin-1 activates two independent signaling
pathways, one through Syk and one through Raf-1, which
are important for protection against fungi.
PAMPs other than b-glucans and a-mannans are also
expressed in fungal cell walls and include TLR2 and TLR6
ligands (31, 32). The TLR2 signaling is thought to collabo-
rate with Dectin-1 signaling, resulting in the amplification of
the Dectin-1 signaling (3). The Syk-independent Raf-1 path-
way is thought to be important for the crosstalk between
TLR and Dectin-1 signaling by inducing p65 acetylation and
by repressing Syk-induced RelB (30).

Fig. 1. Upon b-glucan binding, Dectin-1 recruits Syk to the ITAM, following the activation of the CARD9–BCL10–MALT1 (CBM) complex. ROS
production is also induced in a Syk-dependent manner, resulting in fungal killing in inflammasomes and the activation of caspase-1. Raf-1 is
activated in a Syk-independent manner. Similar to Dectin-1, Syk is recruited to the ITAM of the FcRc chain upon a-mannan binding to Dectin-2
and activates the CBM complex downstream. TLR-2 ligands (e.g. proteoglycans [PG]) are also expressed in fungal cell walls and the TLR2–TLR6
complex activates the CBM complex through activation of MyD88. Then, the CBM complex activates NF-jB to activate cytokine genes including
pro-IL-1b, IL-23 and IL-12. Raf-1 also promotes NF-jB activation by enhancing phosphorylation of p65. MAPKs such as p38 and Erk are also
activated in a Syk- and Myd88-dependent manner, although this activation is not required for the cytokine production. IL-23 and IL-1b promote
the differentiation of Th17 cells, and IL-17A from Th17 cells recruits neutrophils to the inflammatory sites and activates T cells and B cells,
contributing to the eradication of fungi. A small amount of IL-12 is also produced through activation of NF-jB and induces Th1 cell differentiation.
IFN-c from these cells activates macrophages, contributing to fungal eradication. Dectins also stimulate production of other cytokines, such as
TNF, IL-2, IL-6 and IL-10 (data not shown).
470 Dectin-1 and Dectin-2 in innate immunity
The roles of Dectin-1 and Dectin-2 in host defense against
fungal infection
Dectin-1-deficient mice were more susceptible to P. carinii.
ROS production was abolished in Dectin-1-deficient alveolar
macrophages. On the other hand, production of pro-
inflammatory cytokines such as TNF or IL-12 was not
affected by the Dectin-1 mutation upon treatment with
P. carinii, suggesting that the Dectin-1-induced oxidative
burst is important for fungal eradication (33). However, the
mechanism of ROS production via activation of Dectin-1
remains to be elucidated. ROS induces maturation of IL-1b
through inflammasome-mediated activation of Caspase-1,
that is important for the development of inflammation and
Th17 cell differentiation (13).
Dectin-1-deficient mice also showed increased susceptibil-
ity to intravenous C. albicans infection, with enhanced fungal
dissemination in the gastrointestinal tract and kidney (12).
ROS and TNF production were significantly reduced in
Dectin-1-deficient macrophages and recruitment of neutro-
phils and macrophages into the peritoneal cavity was
reduced in Dectin-1-deficient mice. However, using another
C. albicans strain, Dectin-1-deficient mice showed normal
susceptibility to this fungus both in vivo and in vitro (13).
In the latter case, neither cytokine production nor ROS pro-
duction was dependent on Dectin-1. Because this C. albicans
could bind to Dectin-1-deficient macrophages, it is suggested
that receptors other than Dectin-1 are used for the binding.
Thus, the importance of Dectin-1 in the host defense against
C. albicans may differ depending on the strains.
The importance of Dectin-1 is also shown in the defense
against Aspergillus fumigatus (12, 34). Dectin-1-deficient mice
showed decreased survival upon infection with A. fumigatus
associated with decreased production of cytokines and che-
mokines, reduced neutrophil recruitment and impaired ROS
production. In humans, a mutation in the Dectin-1 gene is
reported to cause recurrent mucosal candidiasis associated
with poor cytokine responses (35). Furthermore, polymor-
phisms in DECTIN-1 Y238X are associated with increased
candida colonization and invasive aspergillosis in hematopoi-
etic stem cell-transplanted recipients (36–38), suggesting that
Dectin-1 also plays important roles for the defense against
fungal infection in humans.
On the other hand, Dectin-2-deficient mice showed de-
creased survival of the infection of three different strains
C. albicans due to the increased fungal growth in the kidney
(14). Thus, Dectin-2 seems to play more important roles for
the defense against C. albicans, probably because mannans,
but not b-glucans, are exposed on the outer most layer of the
fungal cell wall. Because human Dectin-2 also has EPN motif
which is responsible for mannose recognition (22, 39), it is
likely that Dectin-2 also plays an important role for the anti-
fungal immunity in humans.
Interestingly, cytokines, such as IL-6, TNF and IL-23,
which are induced by the Dectin-1 signal, preferentially in-
duce Th17 differentiation (2). This makes a clear contrast to
TLR9, which induces Th1 cell differentiation (Fig. 1). Further-
more, Robinson et al. (26) reported that a specific mAb to
Dectin-2 could suppress not only IL-2, IL-10 and TNF pro-
duction from BMDCs induced by C. albicans but also Th17
cell development during systemic C. albicans infection. Saijo
et al. (14) have also shown the importance of Dectin-2 in the
differentiation of Th17 cells upon infection with the yeast form
of C. albicans; Th17 cells were preferentially induced by the
C. albicans-treated BMDC culture supernatant, whereas
Th17 cell differentiation disappeared in Dectin-2-deficient
BMDCs. Thus, both Dectin-1 and Dectin-2 signaling prefer-
entially induce Th17 cell differentiation. Although Dectin-1
and Dectin-2 signaling also induces Th1 cell differentiation
as a minor response, the mechanism balancing Th1 and
Th17 cell differentiation is still unknown.
It was shown using a Dectin-2-sensitive candida strain that
cytokine production such as TNF and IL-12 induced by the
yeast form was totally lacking in Dectin-2-deficient BMDCs,
Downloaded from https://academic.oup.com/intimm/article/23/8/467/673118 by guest on 17 October 2020
whereas only a partial decrease was observed in hyphal
form-treated BMDCs (14). These observations suggest
that the yeast form expresses only mannans on the cell
wall surface as functional ligands, whereas the hyphal
form expresses other ligand(s). Because hypha-induced
cytokine production is dependent on CARD9 and MyD88,
these ligands may bind TLR2 and TLR6 (40, 41). Hyphal
C. albicans-treated BMDC culture supernatant also induced
Th17 cell differentiation from naive T cells. This differentiation,
however, was not inhibited by Dectin-1 deficiency and only
partially inhibited by Dectin-2 deficiency, suggesting involve-
ment of other receptor(s). The responsible receptors that
recognize the hyphal form of C. albicans for the induction of
Th17 cells remain to be elucidated.
The importance of IL-17A and/or IL-17F in host defense
against C. albicans has been suggested using IL-
17RA-deficient mice and IL-23p19-deficient mice (42, 43).
Recently, we demonstrated that IL-17A-deficient mice, but
not IL-17F-deficient mice, show increased susceptibility to
systemic C. albicans infection, indicating the importance of
IL-17A for protection against this pathogen (14). The impor-
tance of Th17 cells for the defense against fungal infection
is also suggested in humans; hyper-IgE syndrome patients
with autosomal dominant mutations in the signal transducer
and activator of transcription 3 (STAT3) gene, by which
Th17 cell differentiation is suppressed, are associated with
chronic mucocutaneous candidiasis (CMC) (44, 45). Fur-
thermore, people with an autosomal dominant mutation in
the IL-17F gene as well as with a recessive mutation in the
IL-17RA gene show CMC (46). CMC is also observed in
autoimmune regulator (AIRE) mutation-induced autoim-
mune polyendocrinopathy candidiasis ectodermal dystro-
phy (APECED) patients or thymoma patients with high
levels of autoantibodies to IL-17F, suggesting that IL-17F is
important for the protection against mucosal candida infec-
tion (47). Although anti-IL-17A was also increased in these
patients, the correlation between CMC was more clearly
observed in anti-IL-17F levels. Thus, IL-17A is important for
systemic candidiasis, whereas IL-17F is more important in
mucocutaneous candida infection. This is probably
because IL-17F is preferentially produced by mucosal
epithelial cells (48).
IL-22, one of Th17 cytokines, is also suggested to be in-
volved in the host defense against fungal infection. Anti-IL-22
levels were correlated with the development of CMC in
APECED patients (47). Because normal IL-17A responses

were observed in many APECED patients with CMC, IL-22
was suggested to play more important role than IL-17A.
Blocking candida-mannan/b-glucan-induced prostaglandin E2
production with non-steroidal anti-inflammatory drugs sup-
pressed IL-17A and IL-22 secretion in human PBMCs, causing
increased susceptibility to candida infection (9). IL-22 medi-
ates protection against C. albicans in IL-17RA-deficient mice
by controlling the growth of infecting yeasts as well as by con-
tributing to the host’s epithelial integrity (49). IL-22 is especially
important in mucoepithelial infection because IL-22 receptor is
expressed exclusively in the digestive, skin and respiratory
organ systems (50).
The mechanisms that IL-17A and IL-17F use to control
fungal infection have not been clarified. Because IL-17A is
important for the generation and recruitment of neutrophils
to inflammatory sites (51) and neutrophils are important in
protection against fungal infection, this function of IL-17A
may be related to the protective activity. Actually, decreased
neutrophil recruitment to the peritoneal cavity was observed
in Dectin-1-deficient mice upon intraperitoneal infection with
C. albicans (12). However, no such reduction of neutrophil
infiltration was observed in kidneys of Dectin-2-deficient
mice infected intravenously (14), leaving the importance of
IL-17A-induced neutrophil recruitment in candida eradication
to be fully understood. Because IL-17A is also important for
the activation of T cells and B cells, it is possible that IL-17A
is involved in fungal eradication through activation of
acquired immunity. Although IL-17A and IL-17F can induce
innate anti-microbial peptides such as b-defensins, the roles
of b-defensins in systemic candidiasis are not clear at pres-
ent. Excess Th17 cytokines, however, promote inflammation
and impair anti-fungal immune responses when mice are
infected gastrointestinally (52).
Concluding remarks
Several groups suggest the involvement of Dectin-1 in host de-
fense against Mycobacterium tuberculosis (53–55), although
another group did not find any protective function (56). Be-
cause M. tuberculosis does not synthesize b-glucans, the
presence of other Dectin-1 ligand(s) is suggested. Dectin-2
also binds several bacteria and parasites including M. tu-
berculosis, Streptococcus pneumonia, and Schistosoma
mansoni (22, 57). This receptor also recognizes house dust
mites and stimulates production of leukotrienes (58), sug-
gesting that Dectin-2 may also be involved in host defense
and allergic responses against these organisms. Thus,
Dectin-1 and Dectin-2 have a wide range of function and
may have a broader range of ligands including endogenous
ligands. Unveiling these receptor–ligand relationships will
make it possible for us to develop better therapeutics to
treat infections and allergy caused by these organisms.
Funding
This work is supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan (20220009, 23390101), JST CREST, JST PRESTO pro-
gram and the Promotion of Basic Research Activities for In-
novative Biosciences program.
Dectin-1 and Dectin-2 in innate immunity 471
References
1 Figdor, C. G., van Kooyk, Y. and Adema, G. J. 2002. C-type lectin
receptors on dendritic cells and Langerhans cells. Nat. Rev.
Immunol. 2:77.
2 LeibundGut-Landmann, S., Gross, O., Robinson, M. J. et al. 2007.
Syk- and CARD9-dependent coupling of innate immunity to the
induction of T helper cells that produce interleukin 17. Nat.
Immunol. 8:630.
3 Drummond, R. A., Saijo, S., Iwakura, Y. and Brown, G. D. 2011.
The role of Syk/CARD9 coupled C-type lectins in antifungal
immunity. Eur. J. Immunol. 41:276.
4 Poulain, D. and Jouault, T. 2004. Candida albicans cell wall
glycans, host receptors and responses: elements for a decisive
crosstalk. Curr. Opin. Microbiol. 7:342.
5 Cambi, A., Netea, M. G., Mora-Montes, H. M. et al. 2008. Dendritic
cell interaction with Candida albicans critically depends on
Downloaded from https://academic.oup.com/intimm/article/23/8/467/673118 by guest on 17 October 2020
N-linked mannan. J. Biol. Chem. 283:20590.
6 Netea, M. G., Brown, G. D., Kullberg, B. J. and Gow, N. A. 2008.
An integrated model of the recognition of Candida albicans by the
innate immune system. Nat. Rev. Microbiol. 6:67.
7 Lee, S. J., Zheng, N. Y., Clavijo, M. and Nussenzweig, M. C. 2003.
Normal host defense during systemic candidiasis in mannose
receptor-deficient mice. Infect. Immun. 71:437.
8 van de Veerdonk, F. L., Marijnissen, R. J., Kullberg, B. J. et al.
2009. The macrophage mannose receptor induces IL-17 in
response to Candida albicans. Cell Host Microbe 5:329.
9 Smeekens, S. P., van de Veerdonk, F. L., van der Meer, J. W.,
Kullberg, B. J., Joosten, L. A. and Netea, M. G. 2010. The Candida
Th17 response is dependent on mannan- and beta-glucan-
induced prostaglandin E2. Int. Immunol. 22:889.
10 Jouault, T., El Abed-El Behi, M., Martinez-Esparza, M. et al. 2006.
Specific recognition of Candida albicans by macrophages
requires galectin-3 to discriminate Saccharomyces cerevisiae
and needs association with TLR2 for signaling. J. Immunol.
177:4679.
11 Yamasaki, S., Matsumoto, M., Takeuchi, O. et al. 2009. C-type
lectin Mincle is an activating receptor for pathogenic fungus,
Malassezia. Proc. Natl Acad. Sci. USA 106:1897.
12 Taylor, P. R., Tsoni, S. V., Willment, J. A. et al. 2007. Dectin-1 is
required for beta-glucan recognition and control of fungal
infection. Nat. Immunol. 8:31.
13 Saijo, S., Fujikado, N., Furuta, T. et al. 2007. Dectin-1 is required
for host defense against Pneumocystis carinii but not against
Candida albicans. Nat. Immunol. 8:39.
14 Saijo, S., Ikeda, S., Yamabe, K. et al. 2010. Dectin-2 recognition of
alpha-mannans and induction of Th17 cell differentiation is essential
for host defense against Candida albicans. Immunity 32:681.
15 Ariizumi, K., Shen, G. L., Shikano, S. et al. 2000. Identification of
a novel, dendritic cell-associated molecule, dectin-1, by sub-
tractive cDNA cloning. J. Biol. Chem. 275:20157.
16 Taylor, P. R., Brown, G. D., Reid, D. M. et al. 2002. The beta-glucan
receptor, dectin-1, is predominantly expressed on the surface
of cells of the monocyte/macrophage and neutrophil lineages.
J. Immunol. 169:3876.
17 Brown, G. D. and Gordon, S. 2001. Immune recognition. A new
receptor for beta-glucans. Nature 413:36.
18 Ariizumi, K., Shen, G. L., Shikano, S. et al. 2000. Cloning of
a second dendritic cell-associated C-type lectin (dectin-2) and its
alternatively spliced isoforms. J. Biol. Chem. 275:11957.
19 Taylor, P. R., Reid, D. M., Heinsbroek, S. E., Brown, G. D., Gordon, S.
and Wong, S. Y. 2005. Dectin-2 is predominantly myeloid
restricted and exhibits unique activation-dependent expression
on maturing inflammatory monocytes elicited in vivo. Eur.
J. Immunol. 35:2163.
20 Sato, K., Yang, X. L., Yudate, T. et al. 2006. Dectin-2 is a pattern
recognition receptor for fungi that couples with the Fc receptor
gamma chain to induce innate immune responses. J. Biol. Chem.
281:38854.
21 Brown, G. D. and Gordon, S. 2003. Fungal beta-glucans and
mammalian immunity. Immunity 19:311.
472 Dectin-1 and Dectin-2 in innate immunity
22 McGreal, E. P., Rosas, M., Brown, G. D. et al. 2006. The
carbohydrate-recognition domain of Dectin-2 is a C-type lectin
with specificity for high mannose. Glycobiology 16:422.
23 Cutler, J. E. 2001. N-glycosylation of yeast, with emphasis on
Candida albicans. Med. Mycol. 39 (Suppl. 1):75.
24 Shibata, N., Kobayashi, H., Okawa, Y. and Suzuki, S. 2003.
Existence of novel beta-1,2 linkage-containing side chain in the
mannan of Candida lusitaniae, antigenically related to Candida
albicans serotype A. Eur. J. Biochem. 270:2565.
25 Rogers, N. C., Slack, E. C., Edwards, A. D. et al. 2005. Syk-
dependent cytokine induction by Dectin-1 reveals a novel pattern
recognition pathway for C type lectins. Immunity 22:507.
26 Robinson, M. J., Osorio, F., Rosas, M. et al. 2009. Dectin-2 is
a Syk-coupled pattern recognition receptor crucial for Th17
responses to fungal infection. J. Exp. Med. 206:2037.
27 Bertin, J., Guo, Y., Wang, L. et al. 2000. CARD9 is a novel
caspase recruitment domain-containing protein that interacts
with BCL10/CLAP and activates NF-kappa B. J. Biol. Chem.
275:41082.
28 Hara, H., Ishihara, C., Takeuchi, A. et al. 2007. The adaptor protein
CARD9 is essential for the activation of myeloid cells through ITAM-
associated and Toll-like receptors. Nat. Immunol. 8:619.
29 Gross, O., Gewies, A., Finger, K. et al. 2006. Card9 controls a non-
TLR signalling pathway for innate anti-fungal immunity. Nature
442:651.
30 Gringhuis, S. I., den Dunnen, J., Litjens, M. et al. 2009. Dectin-1
directs T helper cell differentiation by controlling noncanonical NF-
kappaB activation through Raf-1 and Syk. Nat. Immunol. 10:203.
31 Brown, G. D., Herre, J., Williams, D. L., Willment, J. A., Marshall, A. S.
and Gordon, S. 2003. Dectin-1 mediates the biological effects of
beta-glucans. J. Exp. Med. 197:1119.
32 Dennehy, K. M., Willment, J. A., Williams, D. L. and Brown, G. D.
2009. Reciprocal regulation of IL-23 and IL-12 following co-
activation of Dectin-1 and TLR signaling pathways. Eur.
J. Immunol. 39:1379.
33 Franchi, L., Eigenbrod, T., Munoz-Planillo, R. and Nunez, G. 2009.
The inflammasome: a caspase-1-activation platform that regulates
immune responses and disease pathogenesis. Nature Immunol.
10:241.
34 Werner, J. L., Metz, A. E., Horn, D. et al. 2009. Requisite role for
the dectin-1 beta-glucan receptor in pulmonary defense against
Aspergillus fumigatus. J. Immunol. 182:4938.
35 Ferwerda, B., Ferwerda, G., Plantinga, T. S. et al. 2009. Human
dectin-1 deficiency and mucocutaneous fungal infections. N. Engl
J. Med. 361:1760.
36 Plantinga, T. S., van der Velden, W. J., Ferwerda, B. et al. 2009.
Early stop polymorphism in human DECTIN-1 is associated with
increased candida colonization in hematopoietic stem cell trans-
plant recipients. Clin. Infect. Dis. 49:724.
37 van der Velden, W. J., Plantinga, T. S., Feuth, T., Donnelly, J. P.,
Netea, M. G. and Blijlevens, N. M. 2010. The incidence of acute
graft-versus-host disease increases with Candida colonization
depending the dectin-1 gene status. Clin. Immunol. 136:302.
38 Chai, L. Y., de Boer, M. G., van der Velden, W. J. et al. 2011. The
Y238X stop codon polymorphism in the human beta-glucan
receptor dectin-1 and susceptibility to invasive aspergillosis.
J. Infect. Dis. 203:736.
39 Gavino, A. C., Chung, J. S., Sato, K., Ariizumi, K. and Cruz, P. D.
Jr. 2005. Identification and expression profiling of a human C-type
lectin, structurally homologous to mouse dectin-2. Exp. Dermatol.
14:281.
40 Ozinsky, A., Smith, K. D., Hume, D. and Underhill, D. M. 2000.
Co-operative induction of pro-inflammatory signaling by Toll-like
receptors. J. Endotoxin. Res. 6:393.
41 Underhill, D. M., Ozinsky, A., Hajjar, A. M. et al. 1999. The Toll-like
receptor 2 is recruited to macrophage phagosomes and discrim-
inates between pathogens. Nature 401:811.
42 Conti, H. R., Shen, F., Nayyar, N. et al. 2009. Th17 cells and IL-17
receptor signaling are essential for mucosal host defense against
oral candidiasis. J. Exp. Med. 206:299.
43 Huang, W., Na, L., Fidel, P. L. and Schwarzenberger, P. 2004.
Requirement of interleukin-17A for systemic anti-Candida albicans
host defense in mice. J. Infect. Dis. 190:624.
44 Milner, J. D., Brenchley, J. M., Laurence, A. et al. 2008. Impaired
T(H)17 cell differentiation in subjects with autosomal dominant
hyper-IgE syndrome. Nature 452:773.
45 Puel, A., Picard, C., Cypowyj, S., Lilic, D., Abel, L. and
Casanova, J. L. 2010. Inborn errors of mucocutaneous immunity to
Downloaded from https://academic.oup.com/intimm/article/23/8/467/673118 by guest on 17 October 2020
Candida albicans in humans: a role for IL-17 cytokines? Curr. Opin.
Immunol. 22:467.
46 Puel, A., Cypowyj, S., Bustamante, J. et al. 2011. Chronic
mucocutaneous candidiasis in humans with inborn errors of
interleukin-17 immunity. Science 332:65.
47 Kisand, K., Boe Wolff, A. S., Podkrajsek, K. T. et al. 2010. Chronic
mucocutaneous candidiasis in APECED or thymoma patients
correlates with autoimmunity to Th17-associated cytokines.
J. Exp. Med. 207:299.
48 Ishigame, H., Kakuta, S., Nagai, T. et al. 2009. Differential roles of
interleukin-17A and -17F in host defense against mucoepithelial
bacterial infection and allergic responses. Immunity 30:108.
49 De Luca, A., Zelante, T., D’Angelo, C. et al. 2010. IL-22 defines
a novel immune pathway of antifungal resistance. Mucosal
Immunol. 3:361.
50 Aujla, S. J. and Kolls, J. K. 2009. IL-22: a critical mediator in
mucosal host defense. J. Mol. Med. 87:451.
51 Khader, S. A., Gaffen, S. L. and Kolls, J. K. 2009. Th17 cells at the
crossroads of innate and adaptive immunity against infectious
diseases at the mucosa. Mucosal Immunol. 2:403.
52 Zelante, T., De Luca, A., Bonifazi, P. et al. 2007. IL-23 and the Th17
pathway promote inflammation and impair antifungal immune
resistance. Eur. J. Immunol. 37:2695.
53 Lee, H. M., Yuk, J. M., Shin, D. M. and Jo, E. K. 2009. Dectin-1 is
inducible and plays an essential role for mycobacteria-induced
innate immune responses in airway epithelial cells. J. Clin.
Immunol. 29:795.
54 Rothfuchs, A. G., Bafica, A., Feng, C. G. et al. 2007. Dectin-1
interaction with Mycobacterium tuberculosis leads to enhanced IL-
12p40 production by splenic dendritic cells. J. Immunol. 179:3463.
55 Yadav, M. and Schorey, J. S. 2006. The beta-glucan receptor
dectin-1 functions together with TLR2 to mediate macrophage
activation by mycobacteria. Blood 108:3168.
56 Marakalala, M. J., Guler, R., Matika, L. et al. 2010. The Syk/CARD9-
coupled receptor Dectin-1 is not required for host resistance to
Mycobacterium tuberculosis in mice. Microbes Infect. 13:198.
57 Ritter, M., Gross, O., Kays, S. et al. 2010. Schistosoma mansoni
triggers Dectin-2, which activates the Nlrp3 inflammasome and
alters adaptive immune responses. Proc. Natl Acad. Sci. USA
107:20459.
58 Barrett, N. A., Maekawa, A., Rahman, O. M., Austen, K. F. and
Kanaoka, Y. 2009. Dectin-2 recognition of house dust mite triggers
cysteinyl leukotriene generation by dendritic cells. J. Immunol.
182:1119.