Dectin-1 and Dectin-2 in innate immunity against fungi
Shinobu Saijo
1
2
Yoichiro Iwakura
0
3
0
Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
,
Tokyo108-8639
,
Japan
1
PRESTO, Japan Science and Technology Agency (JST)
,
Saitama 332-0012
,
Japan
2
Department of Molecular Immunology, Medical Mycology Research Center, Chiba University
,
Chiba 260-8673
,
Japan
3
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency
,
Saitama 332-0012
,
Japan
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.
Introduction
The C-type lectins are one of the pattern recognition
receptors (PRRs) with lectin-like carbohydrate recognition domains
(CRDs) in their extracellular carboxy-terminal domains (1, 2).
Some C-type lectin family members recognize the
carbohydrate 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
receptors (TLRs), C-type lectins that recognize PAMPs are also
involved 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
innate 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 (46). However, MR-deficient
mice show normal host defense during systemic candidiasis
and macrophages isolated from MR-deficient mice show
normal 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
recognizes a-mannose structure and is suggested to be involved
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),
respectively, and induce cytokines and reactive oxygen species
(ROS) to protect hosts from fungal infection through activation
of the spleen tyrosine kinase (Syk)caspase recruitment
domain 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 glycosylat (...truncated)