Dendritic cells and epithelial cells: Linking innate and adaptive immunity in asthma

Article (PDF Available)inNature Reviews Immunology 8(3):193-204 · April 2008with148 Reads
DOI: 10.1038/nri2275 · Source: PubMed
Abstract
Dendritic cells (DCs) are generally held responsible for initiating and maintaining allergic T helper 2 (T(H)2)-cell responses to inhaled allergens in asthma. Although the epithelium was initially considered to function solely as a physical barrier, it is now seen as a central player in the T(H)2-cell sensitization process by influencing the function of DCs. Clinically relevant allergens, as well as known environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells and DCs. A better understanding of these interactions, ascertained from human and animal studies, might lead to better prevention and treatment of asthma.
Asthma is a chronic inflammatory disease of the lungs
that is increasingly observed in developed countries
and that is characterized by recurrent episodes of
wheezing, breathlessness, chest tightness and coughing.
In genetically susceptible individuals, the exposure to a
wide variety of environmental stimuli, such as allergens
(derived, for example, from house-dust mites, molds,
plant pollen and animal dander), infection (particularly
viruses), airborne pollutants (such as tobacco smoke,
diesel particles and ozone), physical stimuli (such as
exercise and cold air) and drugs (for example, aspirin)
can either induce and/or exacerbate the disease
1,2
.
Clinically, two forms of the disease can be distin-
guished, allergic and non-allergic asthma, of which the
former is dependent on the presence of IgE antibodies
specific for common allergens in the lungs. However,
characteristic to both forms of the disease is the airway-
wall accumulation of T helper cells that predominantly
secrete interleukin-4 (
IL-4), IL-5, IL-13 and tumour-
necrosis factor (TNF) a phenotype consistent with
that of inflammatory T helper 2 (T
H
2) cells
3,4
.
Studies in animal models of asthma have shown that
T
H
2 cells have a predominant role in disease pathogen-
esis (FIG. 1) by inducing the survival and recruitment
of eosinophils and mast cells, by inducing goblet-cell
hyperplasia, and by causing bronchial hyper-reactivity. That
T
H
2 cells cause bronchial hyper-reactivity is explained by
the fact that the T
H
2-cell-assoicated cytokines IL-9 and
IL-13 can change the excitability of bronchial smooth-
muscle cells, thereby inducing bronchoconstriction in
response to various nonspecific stimuli, such as cold air
or physical exercise. Particularly in human asthma, the
degranulation and production of T
H
2-cell-associated
cytokines by mast cells that occurs in the smooth-muscle
layer surrounding the airway wall are important in causing
this bronchial hyper-reactivity
5
.
In developed countries, 30% of the population is
atopic, but only 10–12% of the population actually suffers
from asthma
6
; this implies that allergic T
H
2-cell sensitiza-
tion and the presence of an IgE response to an inhaled
allergen are only risk factors rather than the causative
factors of asthma. It is therefore crucial to identify the
enhancing genetic or environmental factors that might
promote asthma in a sensitized individual. Efforts to
identify asthma susceptibility genes on a genome-wide
basis have identified genes that are associated with allergy
per se, or with the tendency to develop bronchial hyper-
reactivity (reviewed in REFS 1,7). The products of many
of these susceptibility genes are expressed either by skin
8
or lung epithelial cells and can influence the way in which
epithelial cells recover following an inflammatory insult
9
,
whereas the products of other susceptibility genes influ-
ence the way in which allergens are recognized by innate
immune cells.
Similarly, it is immediately clear from analysis of the
common characteristics of the most relevant allergens
that some allergens have the potential to modify the
function of the epithelium barrier or to activate airway
epithelial cells
10
or innate or adaptive immune cells
(TABLE 1). For example, the Der p 1 allergen, a major
allergen of the house-dust mite Dermatophagoides
pteronyssinus, increases the permeability of the bronchial
*Department of Respiratory
Diseases, Laboratory of
Immunoregulation and
Mucosal Immunology,
University Hospital Ghent,
Belgium.
Department of Pulmonary
Medicine, Erasmus University
Medical Center, Rotterdam,
The Netherlands.
Correspondence to B.N.L.
e‑mail:
bart.lambrecht@ugent.be
doi:10.1038/nri2275
T
H
2 cells
(T helper 2 cells). A type of
T cell that, through the
production of interleukin-4
(IL-4), IL-13 and other
cytokines, can help B cells to
produce IgE and other
antibodies and, through the
secretion of IL-5, IL-3 and
others, can promote increased
numbers of eosinophilic
granulocytes (eosinophils),
basophils and mast cells.
Hyperplasia
An increase in the number of
cells in a tissue or organ.
Dendritic cells and epithelial cells:
linking innate and adaptive immunity
in asthma
Hamida Hammad* and Bart N. Lambrecht*
Abstract | Dendritic cells (DCs) are generally held responsible for initiating and maintaining
allergic T helper 2 (T
H
2)-cell responses to inhaled allergens in asthma. Although the
epithelium was initially considered to function solely as a physical barrier, it is now seen as a
central player in the T
H
2-cell sensitization process by influencing the function of DCs.
Clinically relevant allergens, as well as known environmental and genetic risk factors for
allergy and asthma, often interfere directly or indirectly with the innate immune functions of
airway epithelial cells and DCs. A better understanding of these interactions, ascertained
from human and animal studies, might lead to better prevention and treatment of asthma.
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Goblet cell
Goblet-cell
hyperplasia
T
H
2 cell
Eosinophil
Smooth-
muscle
cell
Airway
Epithelial
cell
Epithelial-cell
damage
Airway-wall
remodelling
IL-4,
IL-9,
IL-13
IL-4,
IL-13,
TNF
IL-5, IL-9,
IL-13, TNF
IL-5,
GM-CSF
Blood vessel
ICAM1
VCAM1
VLA4
Epithelial–
mesenchymal
trophic unit
Bronchial
hyper-reactivity
Survival and activation
of eosinophils
Vessel-wall priming for
inflammatory-cell recruitment
Mucus
Bronchial hyper-reactivity
The tendency of an asthmatic’s
immune system to overreact to
a variety of nonspecific stimuli.
This is measured in a
physiology laboratory by
changes in airway resistance
induced by pharmacological
stimuli, such as methacholine
or histamine, and expressed as
the concentration of a stimulus
that induces a 20% drop in
lung function (that is, the PC20
value).
epithelium, as measured by a decrease in transepithelial
electrical resistance
11
, and activates airway epithelial cells
and innate and adaptive immune cells
12–17
.
These findings have raised the concept that the
sensitization and progression towards asthma are fun-
damentally influenced by a fine balance between the
functions of innate immune cells, epithelial cells and the
induction of adaptive immunity (as determined by the
balance between T
H
2 cells and regulatory T cells; BOX 1).
At the crossroads of innate and adaptive immunity, and
located alongside epithelial cells in the airways, dendritic
cells (DCs) have an important role in determining how
allergic immune responses are initiated and perpetuated.
In this Review, we discuss how the interplay between
innate and adaptive immunity influences the crosstalk
between epithelial cells and DCs in the induction of
asthma. We also discuss how established allergic inflam
-
mation influences this crosstalk. A better understanding
of these interactions will provide a framework for the
rational design of asthma therapy.
Uptake and transport of inhaled allergens
Sampling antigen from the airway lumen. The conducting
airways are lined with a mucociliary blanket and are com-
posed of airway epithelial cells that are connected by tight
junctions and zonula occludens proteins. The epithelial-
cell layer acts as a molecular sieve that excludes inhaled
antigens and pathogens based on their molecular weight.
Mucosal DCs are situated in the basolateral space, only
separated from the inhaled air by the epithelium tight-
junction barrier (FIG. 2). In the airways, as well as in the
gut, DCs can extend their processes between epithelial
cells directly into the airway lumen. This ‘periscope’
function is constitutively active in the airway mucosal
DC population, providing a mechanism for continuous
immune surveillance of the airway luminal surface
18,19
(see Supplementary information S1 (Movie)). At least
in mouse lungs, intraepithelial CD103
+
DCs express the
tight-junction proteins claudin-1, claudin-7 and zonula-2,
which form tight junctions with airway epithelial cells,
thereby explaining how DCs can sample the content of
the airway lumen without disturbing the function of the
epithelium barrier
20
.
When large fluorescently labelled antigens are
injected into the lungs of mice, different subsets of DCs
(BOX 2) become antigen positive in the draining medi-
astinal lymph nodes as early as 12 hours after antigen
administration
21,22
. There are several mechanisms by
which the inhaled antigens could reach the lymph nodes
(for a more detailed discussion on this topic, see REF. 23).
Most of the experimental evidence suggests that antigen
is taken up by DCs in the lung and that these cells then
migrate in a CC-chemokine receptor 7 (CCR7)- and
CCR8-dependent manner to the draining mediastinal
lymph nodes, which is analogous to the directed migra-
tion of skin DCs
21,24,25
. It is still unclear exactly where and
by which DC subset the inhaled antigen is sampled from
the airways, as both mucosal DCs that line the conduct-
ing airways and DCs that are situated in the alveolar wall
are exposed to inhaled antigens
23,26
.
In addition to cell-mediated transport, the tight-
junction barrier might act as a molecular sieve that allows
the passive leakage of smaller antigens into the afferent
lymph vessels. Antigen sampled in such a passive manner
might gain access to resident DCs in the draining lymph
nodes, such as CD8α
+
DCs or plasmacytoid DCs (pDCs)
23
.
Although there is indeed evidence for the passive trans-
fer of fluorescently labelled molecules to the mediastinal
lymph nodes, no studies to date have demonstrated that
antigen that reaches the resident DCs in this manner
can result in the induction of T-cell division
22,24
. This is
clearly different from the immune response induced fol-
lowing footpad injection of mice, in which the passive
acquisition of antigen by skin-resident DCs leads to T-cell
division
27
. This differential outcome might be explained
by the fact that following skin puncture, the physical
Figure 1 | A central role for inflammatory T
H
2 cells in asthma. Asthma is
characterized by the infiltration of T helper 2 (T
H
2)-type cells, eosinophils, and mast cells
(not shown) to the airway wall. The T
H
2-cell-associated cytokines interleukin-4 (IL-4), IL-5,
IL-9, IL-13 and tumour-necrosis factor (TNF) have an important role in the pathogenesis
of allergic asthma, as shown by their induction of most of the salient features of asthma,
such as goblet-cell hyperplasia, airway-wall remodelling and bronchial hyper-reactivity.
T
H
2-cell-associated cytokines are known to induce changes in blood vessels that lead to
the upregulation of intercellular adhesion molecule 1 (ICAM1) and vascular cell-adhesion
molecule 1 (VCAM1). This leads to the recruitment of very late antigen 4 (VLA4)-
expressing eosinophils into the airway wall. These factors also induce the survival and
activation of eosinophils. In addition to the effects of T
H
2-cell-associated cytokines on
airway pathology, IL-4 and IL-13 are responsible for promoting immunoglobulin class
switching to the IgE heavy chain, allowing for the production of IgE by B cells, a feature of
allergic asthma (not depicted). T
H
2-type cytokines lead to stimulation of the epithelial–
mesenchymal tropic unit, thus stimulating collagen deposition.
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Atopic
The propensity of an individual
to develop allergic diseases,
such as asthma, atopic
dermatitis, food allergy or hay
fever. It is defined operationally
by elevations in serum levels of
IgE reactive with allergens or
by skin-test reactivity to
allergens.
Transepithelial electrical
resistance
An assay in which epithelial-
cell monolayers are grown
on a permeable membrane
and exposed to a high
concentration of electrolytes
on the basolateral side, and a
low concentration on the
apical side, thereby generating
an electrochemical gradient.
The electrical resistance
between basolateral and
apical side is a measure of the
permeability of the epithelium.
Tight junction
A belt-like region of adhesion
between adjacent epithelial or
endothelial cells that regulates
paracellular flux. Tight-junction
proteins include the integral
membrane proteins occludin
and claudin, in association with
cytoplasmic zonula occludens
proteins.
barrier is artificially breached by a needle puncture, caus-
ing some degree of damage and leading to the release
of necrotic-cell debris that could artificially activate
the innate immune system. Studies using inhaled or
aspirated antigen are less damaging as no injection is
given, and therefore probe the function of steady state
DCs in a more physiological manner
21,28
.
Disruption of the epithelial-cell barrier. Although the
sampling function of airway DCs ensures that virtually
any inhaled protein will be recognized and presented
to T cells following inhalation, some antigens contain
motifs that facilitate their access to DCs, which possibly
explains why they can act as immunogens. Most of the
clinically relevant allergens (such as Der p 1, spores from
Aspergillus spp.
29
and ragweed and birch pollen
30
) have
serine and cysteine protease enzymatic activity that could
promote the paracellular access to intraepithelial DCs
by cleaving the tight-junction occludin proteins, several
claudin family members, and zonula occuldens 1 (REF. 30)
(TABLE 1)
. Other allergens that lack protease activity, such
as cockroach-derived allergens, can increase epithelium
permeability indirectly through the induction of the
angiogenic cytokine vascular endothelial growth factor
(VEGF), mainly known for its potential to induce vascu
-
lar permeability
31
. Interestingly, overexpression of VEGF
under the control of a lung-specific promoter resulted
in the promotion of T
H
2-cell sensitization to otherwise
harmless antigens
32
. Whether the mechanism by which
allergens increase airway permeability and thereby
gain access to intraepithelial DCs is subject to genetic
polymorphism is currently unknown, although some of
the atopy and asthma susceptibility genes, regulate the
function of the epithelium barrier.
Exposure to cigarette smoke is a known environ-
mental risk factor for T
H
2-cell sensitization to inhaled
allergens. Inhaled smoke synergizes with Der p 1 to
decrease epithelium barrier function in an active proc-
ess that involves the activation of intracellular signalling
cascades
33
. The same effect is seen with ozone, another
environmental T
H
2-cell sensitizer
34
.
DCs and T
H
2-cell sensitization
Inhalation tolerance. Despite the fact that most inhaled
antigens are transported to the lymph nodes by lung-
derived DCs, the usual outcome following the inhalation
of harmless protein antigen is the induction of toler-
ance. When the model antigen ovalbumin (OVA) is
introduced into the airways of naive mice, it renders
the mice tolerant to a subsequent immunization with
OVA in alum
adjuvant, and effectively inhibits the
development of allergic airway inflammation
22,35–38
.
Experiments in which naive OVA-specific T-cell recep
-
tor (TCR)-transgenic T cells were adoptively transferred
before antigen inhalation showed that the induction of
tolerance is accompanied by the vigorous proliferation
of naive T cells even when low doses of the antigen are
given, implying that at least the antigen is presented
by lung-derived DCs to T cells in conjunction with
co-stimulatory molecules
21,22,39
.
One possible explanation is that, in naive mice, harm
-
less antigens encountered by lung-derived DCs cannot fully
activate the DCs to induce an effective T-cell response
40,41
.
These partially mature DCs would then induce an abortive
Table 1 | Allergens that depend on proteolytic activity for affecting the DC–epithelial-cell interaction
Allergen Enzyme Mode of action Effect References
House-dust mite Der p 1
Der p 9
Cleavage of tight-junction molecules (occludin, claudin) Increase in epithelium permeability 11
Activation of PAR2 Epithelial-cell activation, induction of
GM-CSF production
17
Cleavage of complement components (C5, C3) Recruitment of innate immune cells 128
DC activation T
H
2-cell polarization 13
Cleavage of DC-SIGN and DC-SIGN-R
Failure to induce IL-10? 58
Cleavage of CD40 Failure to induce IL-12 59
Production of CCL17 and CCL22 by DCs Recruitment of T
H
2 cells 14
Cleavage of CD25 T-cell activation 129
Cleavage of CD23 Stimulation of IgE production by B cells 130
Aspergillus fumigatus
and Aspergillus oryzae
Asp f 5
Asp f 6
Asp f 11
Cleavage of tight-junction molecules Increase in epithelium permeability 29
Induction of IL-25 Promotion of T
H
2-cell responses 81
Induction of chemokines Recruitment of T
H
2 cells and
eosinophils
10,57
Activation of unknown PAR Epithelial-cell activation? 57
Ragweed pollen
Birch pollen
Amb a
Bet v
Cleavage of tight-junction molecules Increase in epithelium permeability 30
Cockroach allergens Bla g Cleavage of tight-junction molecules Increase in epithelium permeability 31
Activation of PAR2 Epithelial-cell activation 131
CCL, CC-chemokine ligand; DC, dendritic cell; DC-SIGN, DC-specific ICAM3-grabbing non-integrin; GM-CSF, granulocyte/macrophage colony-stimulating factor;
IL, interleukin; PAR, protease-activated receptor; T
H
2 cell, T helper 2 cell.
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Adjuvant
An agent mixed with an
antigen that increases the
immune response to that
antigen after immunization.
immune response by activating T cells that fail to reach the
threshold required for prolonged survival and which are
finally deleted
42
. Alternatively, partially mature DCs could
stimulate the induction of IL-10- and/or transforming
growth factor-
β (TGFβ)-producing regulatory T cells, in
a manner dependent on IL-10 and/or on inducible T-cell
co-stimulator ligand (ICOSL)
36,39,43
.
The process of inhalational tolerance is also influenced
by pDCs (BOX 2). Following inhalation of OVA, medias-
tinal pDCs internalize OVA, but unlike conventional
lung-derived DCs, they do not present the antigen in an
immunogenic manner to CD4
+
T cells
22
. However, func-
tional evidence that these cells do influence pulmonary
adaptive immunity came from experiments in which
pDCs were depleted using antibodies. In pDC-depleted
mice, inhalation tolerance was abolished, whereas
tolerance could be induced by the adoptive transfer of
bone-marrow-derived pDCs that had been cultured with
FMS-related tyrosine kinase 3 ligand (FLT3L)
22
. Similarly,
the T
H
2-cell-like immunopathology induced by respira-
tory syncitial virus was exacerbated when pDCs were
depleted
44
. How exactly the depletion of pDCs results
in T
H
2-cell sensitization is still unresolved, but in vitro
and in vivo data suggest that pDCs directly suppress
the potential of lung-derived myeloid DCs to generate
effector T cells
22,45
.
Both in vitro and in vivo studies have clearly shown
that pDCs can also stimulate the induction of regula-
tory T cells, possibly in an ICOSL-dependent man
-
ner
22,46–48
. Once induced, regulatory T cells could also
induce the production of the tryptophan catabolizing
enzyme indoleamine 2,3-dioxygenase (IDO) through
reverse signalling in pDCs. The downstream tryptophan
metabolites generated by IDO might subsequently exert
an anti-inflammatory and tolerizing effect in the lungs,
by inhibiting T-cell activation
49
.
Activated lung-derived DCs and T
H
2-cell priming. If the
usual outcome of inhalation of antigen is the induction
of tolerance by partially mature lung-derived DCs, it
follows that some degree of lung-derived DC activation
could be sufficient to break tolerance and promote T
H
2-
cell development. Conventional DCs express numerous
pattern-recognition receptors (PRRs), including Toll-like
receptors (TLRs), NOD (nucleotide-binding oligomeri
-
zation domain)-like receptors and C-type lectin receptors
(BOX 3). Studies by Kim Bottomly’s group have elegantly
shown that stimulating TLR4 expressed by lung-derived
DCs with low doses of lipopolysaccharide (LPS) is suffi-
cient to break inhalation tolerance and promote T
H
2-cell
development through a myeloid differentiation primary-
response gene 88 (MyD88)-dependent