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Differential Roles of Lung Dendritic Cell Subsets Against
Respiratory Virus Infection
Tae Hoon Kim and Heung Kyu Lee*
Laboratory of Host Defenses, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon 305-701, Korea
Respiratory viruses can induce acute respiratory disease.
Clinical symptoms and manifestations are dependent on interactions between the virus and host immune system.
Dendritic cells (DCs), along with alveolar macrophages, constitute the first line of sentinel cells in the innate immune response against respiratory viral infection. DCs play an essential role in regulating the immune response by bridging innate and adaptive immunity. In the steady state, lung DCs
can be subdivided into CD103 conventional DCs (cDCs),
CD11b cDCs, and plasmacytoid DCs (pDCs). In the inflammatory state, like a respiratory viral infection, monocyte-derived DCs (moDCs) are recruited to the lung. In inflammatory lung, discrimination between moDCs and
CD11b DCs in the inflamed lung has been a critical challenge in understanding their role in the antiviral response. In
particular, CD103 cDCs migrate from the intraepithelial
base to the draining mediastinal lymph nodes to primarily in+
duce the CD8 T cell response against the invading virus.
Lymphoid CD8α cDCs, which have a developmental rela+
tionship with CD103 cDCs, also play an important role in
viral antigen presentation. Moreover, pDCs have been reported to promote an antiviral response by inducing type I interferon production rather than adaptive immunity. However,
the role of these cells in respiratory infections remains
unclear. These different DC subsets have functional specialization against respiratory viral infection. Under certain viral
infection, contextually controlling the balance of these specialized DC subsets is important for an effective immune re-
sponse and maintenance of homeostasis.
[Immune Network 2014;14(3):128-137]
Keywords: Dendritic cells, Influenza, Respiratory syncytial virus, Lung, Infection
The lung is the essential organ for respiration. Because the
lung mucosal area contacts air for gas exchange, it can be
infected easily by various microbes, such as influenza, respiratory syncytial virus (RSV), pneumococcus, and Aspergillus.
Nevertheless, the lung possesses a sentinel system that identifies these threats and elicits an anti-microbial response. In this
review, we focus on the immune response to respiratory viral
infection, which can induce acute respiratory disease.
Dendritic cells (DCs) participate in the first line of defense
in the innate immune response against respiratory viral
infection. DCs are distributed throughout the entire lung, with
each subset localized to a specific compartment of the organ
(1). In the absence of inflammation, lung DCs can be subdivided into three distinct subsets based on the combined ex+
pression of cell surface markers: CD103 conventional DCs
(cDCs), CD11b cDCs, and plasmacytoid DCs (pDCs). During
inflammation, monocyte-derived DCs (moDCs) are generated
Received on April 29, 2014. Revised on May 22, 2014. Accepted on May 27, 2014.
CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
*Corresponding Author. Heung Kyu Lee, Laboratory of Host Defenses, Graduate School of Medical Science and
Engineering, KAIST, 291 Daehak-ro, Daejeon, Korea. Tel: 82-42-350-4281; Fax: 82-42-350-4240; E-mail:
[email protected]
Abbreviations: DC, dendritic cell; cDC, conventional dendritic cell; pDC, plasmacytoid dendritic cell; moDC, monocyte-derived dendritic cell; Treg, regulatory T cells; PRRs, pattern recognition receptors; TLR, toll-like receptor; DTR, diphtheria toxin receptor; IFN, interferon; Tip-DC, TNF and iNOS derived NO producing dendritic cell
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Lung Dendritic Cell Subsets Regulate Respiratory Virus Infection
Tae Hoon Kim and Heung Kyu Lee
in the lung (2,3) (Table I).
In a respiratory virus infection, one virus can induce different types of immune responses depending on the type of DC
subset activated (4,5). In this process, cell type-specific pattern
recognition receptors (PRRs) may also be involved (6). Each
DC subset expresses different pattern recognition receptors,
thereby enabling the cells to react differently depending on
the type of virus infection (7). In particular, neither a vaccine
nor an effective antiviral therapy is currently available against
RSV infection (8). To development vaccine for RSV infection,
understanding the role of the lung DC subsets is important.
Determining the specialized functions of the various lung DC
subsets is challenging. This review focuses on the distinctive
features and antiviral functions exhibited by the various lung
DC subsets during respiratory virus infection in mice.
Table I. Established phenotype of mouse dendritic cells in the
respiratory tract
DC subset
Phenotypic marker
CD103 cDC
MHC class II+
MHC class II+
MHC class IIlow
BST-2+ (PDCA-1+)
2, 3, 4, 6, 9, 11, 12, 13
CD11b+ cDC
CD103+ conventional dendritic cells
The CD103 CD11b cDC subset shares its origin and function with lymphoid tissue CD8α+ cDCs (9,10). CD103+ cDCs
are primarily distributed to connective tissues. The proportion
of CD103 cDCs among total conventional DCs rarely exceeds 20∼30%. These cells express higher fms-like tyrosine
kinase 3 (Flt3) levels compared to CD11b cDCs and therefore proliferate in response to Flt3 ligand (11). CD103 expression is dependent on the tissue microenvironment and
regulated by local production of the cytokine Csf-2 (GM-CSF)
(12-15). However, CD103-deficient mice do not exhibit major
defects in DC development (16). CD103+ cDCs lack the macrophage-related markers CD11b, CD115, CD172a, F4/80, and
CX3CR1. With the exception of intestinal and pancreatic
CD103+ cDCs, these cells express the C-type lectin receptor
langerin (11,17).
Besides connective tissues, CD103 cDCs are located in
nonlymphoid tissues at the interface with the environment.
Lung CD103 cDCs can be found in the mucosa and vascular
wall (18) (Fig. 1). Following antigen uptake, CD103 cDCs
1, 2, 4, 6, 7, 8, 9, 13
7, 9, 12
2, 4, 7
Figure 1. Different type of DC subsets in the respiratory virus infected
lung. In steady state, the lung contains multiple subsets of DCs, such
as CD103+ cDCs, CD11b+ cDCs, CD8α+ cDCs, and pDCs. CD103+
cDCs are mainly located in mucosal walls, and extend their process
to alveolar space for capture viral antigen. CD11b cDCs are
distributed in lamina propria, which is below the basement
membrane. pDCs are place in conducting airway, parenchyma and
alveolar septa. After viral infection, inflammatory lung was induced
the recruitment of moDCs. And viral antigen uptake migratory DCs
translocate to draining mediastinal lymph nodes via afferent
lymphatics. Migrated DCs can present to naïve T cells. Lymph node
resident CD8α+ DCs can receive antigen from migratory DCs, and
present T cells.
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Lung Dendritic Cell Subsets Regulate Respiratory Virus Infection
Tae Hoon Kim and Heung Kyu Lee
migrate to the T cell zone of draining lymph nodes (10). In
the airways and gut, DCs extend their processes between epithelial cells to contact the airway lumen directly. These airway mucosal DCs can conduct continuous immune surveillance of the airway luminal surface, thereby acting like a periscope (19-21). In mouse lungs, intraepithelial CD103+ cDCs
express the tight-junction proteins claudin-1, claudin-7, and
zonula-2, which form tight junctions with airway epithelial
cells (18). As a result, CD103+ cDCs can sample contents
within the airway lumen without disturbing the function of
the epithelium barrier.
Current reports have shown that, following influenza or
RSV infection, CD103 cDCs migrate from the intraepithelial
base to the draining mediastinal lymph nodes (22,23), where
they mainly present antigen to naïve CD4+ and CD8+ T cells.
However, previous studies demonstrated that antigens are
transferred from migratory DCs to CD8α resident cDCs, and
presented to T cells by antigen-bearing CD8α+ resident cDCs
As previously mentioned, studies have established that
CD103+ cDCs belong to the CD8α+ subset of cDCs (2). Like
lymphoid-derived CD8α cDCs, CD103 cDCs originate exclusively from pre-DCs under the control of Flt3 ligand, inhibitor of DNA protein 2 (Id2), and interferon regulatory protein 8 (Irf8) (11,25). Murphy et al. reported a developmental
relationship between lymphoid organ-resident CD8α cDCs
and nonlymphoid CD103+ cDCs using Batf3-deficient mice
(26). A recent study used heat maps to demonstrate that the
expression of pattern recognition receptors, cytokines, and
chemokine receptors is similar between CD103+ cDCs and
CD8α cDCs (27). In particular, both subsets express TLR3,
TLR11, the scavenger receptor CD36, and C-type lectin Clec9A
(28-31). Desch, et al. showed that mouse lung CD103+ cDCs
selectively express TLR3, while CD11b cDCs express TLR2
and TLR7 (32).
CD103+ cDCs play a nonredundant role in stimulating CD8+
T cell-mediated immunity. Influenza virus infection following
depletion of CD103 cDCs in langerin-diphtheria toxin receptor (langerin-DTR) mice results in severe illness, defective
viral clearance, and abrogated antiviral response due to im+
paired development of influenza virus-specific CD8 T cells
(22). In the Batf3 knockout mouse model, the CD103+
cDC-deficient mice cannot produce CD8 T cell priming in
response to influenza infection (33). CD103 cDCs play an
important role in cross-presentation of apoptotic cell-asso+
ciated antigen to CD8 T cells (25,32). However, whether
CD103 cDCs can induce a cytotoxic T cell response against
RSV infection (similar to other viruses) remains to be
The role of lung CD103 cDCs in the activation of CD4
T cells is unclear. In cutaneous skin infection with Candida
albicans, dermal CD103+ cDCs control the induction of
pathogen-specific CD4 IFN-γ T cells (34). A recent study
using langerin-DTR mice demonstrated that ablation of
CD103+ cDCs inhibited induction of the encephalitogenic
CD4 Th1 response and autoimmune encephalomyelitis
(EAE) (35). However, some studies showed that the CD4
T cell response was independent of CD103 cDCs. Batf3
knockout mice that are deficient in CD103 cDCs can mount
an efficient CD4 T cell response to West Nile virus or autoimmune EAE (14,25). Moreover, ablation of CD103+ cDCs in
langerin-DTR mice did not affect the CD4 T cell response
against Leishmania major infection (36).
CD8α+ cDCs and CD103+ cDCs are thought to participate
in deletional tolerance of self-reactive T cells and the induction of antigen-specific regulatory T cells (Treg) (16).
Splenic DCs captured dying cells and processed, then induced specific tolerance (37,38). A report showed that the
CD103 CD207 subset of splenic CD8α cDCs is responsible for tolerance induction to cell-associated antigens (39).
However, an autoimmune response was not observed in
Batf3 knockout mice that lack CD8α cDCs and CD103
cDCs. Thus, the tolerogenic function of lung CD103+ cDCs
remains to be determined.
CD11b+ conventional dendritic cells
In the lung, CD11b cDCs reside mainly in the lamina propria, which is located below the basement membrane (Fig. 1).
CD11b+ cDCs are heterogeneous and their development depends on both Flt3 and M-CSFR (11). Dependency on
M-CSFR is suggestive of a monocytic origin, and some
non-lymphoid CD11b+ cDCs can be reconstituted by pre-DC.
CD11b cDCs frequently lack CD103 but express CD11b.
Despite this, markers to distinguish the two ontogenically distinct subsets differ between tissues. For instance, expression
of CD64 (FcγRI) helps distinguish between these two subpopulations in muscle, whereas expression of CD103 helps
discriminate between the two CD11b+ DC subsets in the intestinal lamina propria (40,41). Lambrecht et al. recommended detection of CD64 and MAR-1 expression as the most
reliable method to discriminate between monocyte-derived
DCs and CD11b cDCs in the lung and mediastinal lymph
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Lung Dendritic Cell Subsets Regulate Respiratory Virus Infection
Tae Hoon Kim and Heung Kyu Lee
nodes (42).
Because CD11b cDCs are not a homogenous subset, the
exact PRR profile of CD11b+ cDCs is complex. Nevertheless,
these receptors are expressed differentially in CD103 cDCs
and CD8α cDCs (27). Quantitative proteomics has revealed
that splenic CD11b+ cDCs express high levels of cytoplasmic
viral sensors and are potent cytokine producers in the steady
state and upon stimulation (43). Lung CD11b cDCs are major producers of proinflammatory chemokines, including
MCP-1, MIP-1α, MIP-1β, RANTES, and MCP5, attracting inflammatory cells and effector T lymphocytes to the lung (44).
CD11b+ cDCs can capture antigens and migrate from nonlymphoid tissues to regional draining lymph nodes (23).
Research has established that CD8α cDCs and CD103
cDCs play crucial roles in cross-presentation. However, dur+
ing influenza infection, CD103 cDCs and CD11b cDCs are
the primary mediators of antigen presentation to naïve CD8
T cells in the draining lymph nodes (45).
During severe influenza infection, CD11b cDCs, but not
CD103 cDCs or CD8α resident cDCs, accumulate in the
draining lymph nodes to become the predominant DC subset
responsible for stimulating CD8 T cells via the costimulatory
molecule CD70 (46). These contradictory findings could be
attributed to the different viral doses used for infection and
the differential effects of direct DC infection by influenza
virus. Severe viral infection induced CD11b cDCs that were
incapable of antigen presentation to CD8+ T cells. However,
low viral doses enabled directly infected CD11b cDCs to ar+
rive at the draining lymph nodes ready to prime the CD8
T cell response (47). In addition, CD11b cDCs are thought
to play a predominant role in MHC class II presentation, including acting as the predominant presenters of viral antigens
to CD4+ T cells in response to influenza virus infection (45).
CD11b cDCs constantly escape from the blood to the thymus to induce central tolerance, such as clonal deletion of
autoreactive T cells or differentiation of Treg (48,49). CD103+
CD11b cDCs purified from the lamina propria of the small
intestine were found to promote a high level of Treg differentiation relative to lymphoid organ-derived DCs (50,51).
However, the contribution of lung CD11b cDCs in tolerance
has not been established.
In addition to CD103+ cDC-mediated uptake in the air+
ways, CD11b cDCs utilize another pathway to acquire inhaled antigens. TLR4 triggering of epithelial cells caused production of innate proallergic cytokines, including thymic stromal lymphopoietin (TSLP), granulocyte-macrophage col-
ony-stimulating factor (GM-CSF), interleukin-25, and interleukin-33. In the absence of TLR4 on structural, but not hematopoietic cells, CD11b+ cDCs were not recruited or activated
in a chimeric mouse model (52). It is unclear whether lung
CD11b cDCs require epithelial activation as well.
CD11b+ cDCs are essential for the maintenance of inducible bronchus-associated lymphoid tissue (iBALT), a tertiary lymphoid organ (TLO) induced in the lungs after influenza infection (53). After viral clearance, CD11b+ cDCs isolated
from the lungs of mice with iBALT no longer presented viral
antigens to T cells but produced lymphotoxin (LT) β and homeostatic chemokines (CXCL-12, CXCL-13, CCL-19, and
CCL-21) known to contribute to TLO organization. Using the
replication-deficient modified vaccinia virus model, Halle, et
al. described iBALT as a tertiary lymphoid structure that supports the efficient priming of T cells against unrelated inhaled
antigens with DCs required for its maintenance (54).
Plasmacytoid dendritic cells
pDCs are distributed to conducting airways as well as parenchyma and alveolar septa in the lung (Fig. 1). These cells
represent a small subset of DCs, which share a common origin with cDCs. pDCs develop in the bone marrow from a
continuum of Flt3+c-Kitlow progenitors, including lymphoid
progenitors and common DC progenitors (CDPs). Their development proceeds through the putative committed pDC
progenitor and immature pDCs in the bone marrow toward
the mature peripheral pDCs (55). Upregulation of the basic
helix-loop-helix transcription factor (E protein) E2-2 serves as
a key lineage commitment event in pDC development
(56,57). Because E proteins are essential regulators of lymphocyte development, E2-2 activity may underlie the distinct
lymphoid features of pDCs. These cells express low levels
of MHC class II and costimulatory molecules, as well as low
levels of CD11c in the steady state (16). They also express
a narrow range of PRRs, including TLR7 and TLR9.
Generally, pDCs function during the antiviral response to
produce type I IFNs that induce the adaptive immune
response. Some studies have shown that pDCs can trigger an
influenza-specific CD8 T cell response in vitro (58-60).
However, RSV-stimulated pDCs cannot enhance the proliferation and maturation of antigen-specific T cells, but rather
promote direct antiviral activity by secreting type I IFNs (61).
Following influenza infection in vivo, 120G8 CD11c
pDCs accumulate in the lung and lymph nodes carrying viral
nucleoprotein (NP). Depletion of pDCs using 120G8 anti-
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Lung Dendritic Cell Subsets Regulate Respiratory Virus Infection
Tae Hoon Kim and Heung Kyu Lee
bodies did not affect viral clearance or clinical severity during
influenza infection (22). Instead, pDC depletion led to a reduction in antiviral antibody production after clearance of influenza from the lung. However, depletion of pDCs resulted
in decreases viral clearance of RSV infection and exacerbation
of all facets of immune-mediated pathology, including increase of airway hyper-responsiveness, pulmonary inflammation, and mucus production (62,63).
In IkarosL/L mice, expressing low levels of the transcription
factor Ikaros (Ik(L/L)) lack peripheral pDCs, pDCs regulate
T cell accumulation in the bronchoalveolar space during early
influenza virus infection, but are not essential for controlling
this disease (64). These data demonstrated that the antiviral
CD8 T cell response was independent of pDCs. However,
in BDCA2-DTR mice, pDC depletion reduced early type I IFN
production, enhanced early viral replication, and impaired the
survival and accumulation of virus-specific cytotoxic T lymphocytes in systemic MCMV or VSV infection (65).
According to a recent report, pDCs do not appear to influ+
ence viral burden, survival, or virus-specific CD8 T cell response during local HSV infection. In contrast, pDCs were
important for early type I IFN production, NK cell activation,
and CD8 T cell response during systemic HSV infection
(66). These results help elucidate the antiviral role of pDCs
in respiratory virus infection. However, whether pDCs can
differentially respond under different conditions between host
and virus remains to be determined.
Monocyte-derived dendritic cells
Inflammatory moDCs differentiate from circulating Ly6Chi
monocytes (67) (Fig. 1). Recent studies have established that,
under conditions of stress, such as TLR stimulation, early
hematopoietic precursors can differentiate into DCs, bypassing normal growth and differentiation requirements (68,69).
However, the contribution of monocytes and DC-related precursors to the differentiation of lung moDCs in response to
respiratory virus infection remains unclear.
Most inflammatory DCs are characterized by the expression
of Ly6C, CD11b, MHC class II, and intermediate levels of
CD11c (67). Ly6C is a distinct marker of monocytes, but that
is downregulated rapidly in the presence of moDCs
(42,70,71). Therefore, distinguishing inflammatory moDCs
from nonlymphoid CD11b DCs is challenging. As mentioned in the preceding section, one report demonstrated that
staining with the MAR-1 antibody directed against the high
affinity immunoglobulin E (IgE) α chain receptor (FcεRI) is
better than staining for Ly6C (2). A recent study showed that
inflammatory moDCs are recruited to draining lymph nodes
following lipopolysaccharide (LPS) stimulation, and that these
moDCs express the lectin DC-SIGN/CD209, the mannose receptor CD206, and CD14 (71).
Monocytes were originally considered the immediate upstream precursors of cDCs. This hypothesis originated from
studies showing that DCs could be differentiated in vitro from
human blood mononuclear cells using GM-CSF and IL-4 (72).
When monocytes were transferred into mice with an inflammatory milieu dependent on GM-CSF, monocytes produced a distinct type of splenic DC (73). Nowadays, the concept that monocytes are a precursor of inflammatory DCs is
widely accepted. More recent studies have shown that monocytes contribute to cDC development in the steady state
(41,74-76). However, because this review focuses on DC subsets that act against respiratory virus infection, we refer to
mononuclear cell-derived DCs as moDCs in inflammation.
CD11b DCs can produce TNF and iNOS-derived NO during L. monocytogenes infection. These Tip-DCs are dependent on CCR2 and mediate innate immunity against this intracellular bacterial pathogen (77), suggesting that Tip-DCs may
contribute to the elimination of intracellular pathogens.
A recent study identified an uncharacterized zinc finger
transcription factor named zDC (Zbtb46, Btbd4) that is expressed specifically by cDCs and committed cDC precursors
but not by monocytes, pDCs, or other immune cell populations (78,79). zDC-DTR mice treated with diphtheria toxin
eliminated LPS-induced inflammatory moDCs, suggesting that
LPS induced inflammatory moDCs that belong to a real DC
population. However, L. monocytogenes infection-induced
Tip-DCs were not ablated by DT treatment in these mice.
Given this result, Tip-DCs most likely resemble monocytes
more than DCs.
CD11b moDCs are recruited to inflammatory sites in the
lungs following exposure to respiratory antigen or virus.
During influenza infection, moDCs also differentiate from
monocytes in the lung. These trafficking and differentiation
process are dependent on type I IFN signaling and CCR2 during influenza infection (80,81). Some in vitro studies suggested that type I IFN-producing moDCs can regulate viral
replication (82,83); however, whether moDCs participate directly in the antiviral response remains unclear. Interestingly,
CCR2-deficient mice did not exhibit increased influenza viral
Whether moDCs can migrate to draining lymph nodes and
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Lung Dendritic Cell Subsets Regulate Respiratory Virus Infection
Tae Hoon Kim and Heung Kyu Lee
induce the T cell response has not been determined (45,46).
Monocyte-derived CD11c DCs, which express CX3CR1, can
patrol the vessel wall of the pulmonary arterial vasculature
and capture embolic materials. Thus, these cells are essential
and sufficient for priming of naïve T cells in lung draining
mediastinal lymph nodes (84). Some studies have shown that
moDCs may be important for the interaction of effector T
cells present in the infection site instead of the lymph nodes
CD8α dendritic cells
Generally, CD8α+ cDCs do not exist in the lung because
these cells are non-migrating, lymphoid-organ resident DCs.
However, CD8α cDCs are involved in respiratory virus
infection. They can induce the T cell response in mediastinal
lymph nodes. CD8α cDCs constitute 20∼40% of spleen and
lymph node cDCs. Similar to CD103 cDCs, CD8α cDCs
lack expression of CD11b and other macrophage markers.
However, they express high levels of Flt3 and proliferate in
response to Flt3 ligand (87).
Lymphoid resident CD8α+ cDCs are immature in the
steady state, but microbial products can induce maturation of
CD8α cDCs. Lymph node CD8α cDCs are located in the
subcapsular sinus, the site of afferent lymphatic vessel entry
(39,88). After antigen uptake, these CD8α cDCs migrate to
the T cell zone where they present antigens.
As mentioned above, CD8α+ cDCs share their origin and
function with nonlymphoid CD103 cDCs. However, the
function of CD8α cDCs themselves is still unclear. Generation of conditional or knockout mouse models for specific
depletion of CD8α cDCs will aid in our understanding of
the function of these cells. Additional studies are required to
determine whether these cells have a common immediate
precursor and to investigate which cell is the precursor and
progeny for CD8α cDC (89).
Respiratory viruses can induce acute respiratory disease. In
the lung, DCs are the first line of sentinel cells in the innate
immune response against respiratory viral infection, similar to
alveolar macrophages. DCs are crucial in regulating the immune response by bridging innate and adaptive immunity.
These cells can produce inflammatory cytokines and chemokines, as well as migrate to the draining lymph nodes to initiate the adaptive immune response through antigen present-
ation. Lung DCs associated with viral infection can be sub+
divided into CD103 cDCs, CD11b cDCs, pDCs, and
moDCs. Lymphoid CD8α+ cDCs also play an important role
in the antiviral response. These different DC subsets have
functional specialization against respiratory viral infection.
One virus can induce different immune responses depending
on the type of DC subset activated. Moreover, one subset can
react differently depending on the type of virus encountered.
Contextually controlling the balance between these specialized DC subsets is important for an effective antiviral response and maintaining immune homeostasis. Moreover, understanding the differential roles of lung dendritic cell subsets
against respiratory virus infection is a key point to develop
a vaccine.
We thank Sang Eun Oh for her help with the figure. This
work was supported by the National Research Foundation
(NRF-2013R1A1A2063347, NRF-2012R1A1A2046001, NRF2012M3A9B4028274) and the Converging Research Center
Program (2011K000864) funded by the Ministry of Science,
ICT and Future Planning of Korea.
The authors have no financial conflict of interest.
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