Originally published online as doi:10.1189/jlb.0207096 on April 23, 2007
Published online before print April 23, 2007
(Journal of Leukocyte Biology. 2007;82:1-15.)
© 2007
by Society for Leukocyte Biology
Interactions between epithelial cells and leukocytes in immunity and tissue homeostasis
Renat Shaykhiev and
Robert Bals1
Department of Internal Medicine, Division for Pulmonary Diseases, Philipps-Universtät Marburg, Marburg, Germany
1 Correspondence: Department of Internal Medicine, Division of Pulmonology, Hospital of the University of Marburg, Baldingerstrasse 1, 35043 Marburg, Germany. E-mail: bals{at}mailer.uni-marburg.de
ABSTRACT
Epithelial cells (ECs) cover the surfaces of the body such as
skin, airways, or the intestinal tract and provide an important
link between the outside environment and the body interior.
Leukocytes play a critical role in immunity, as they are the
predominant cell population involved in inflammation and the
only cells providing adaptive immune response to pathogenic
microorganisms. ECs and leukocytes form a complex network, which
regulates processes such as host defense, immunity, inflammation,
tissue repair, and cancer growth. One of the most critical functions
of ECs is to keep up a barrier to the outside and to protect
the sensitive immune system from continuous contact with external
microorganisms. An appropriate response to wounding or danger
involves not only killing of microbes but also regulation of
tissue repair and reconstitution of the barrier system. Dysregulated
response to damage represents a pathophysiological mechanism,
which leads to autoimmunity, chronic inflammatory diseases,
and cancer development. The networks described here are involved
in virtually all diseases that take place at body surfaces.
In this article, we develop a concept of epithelial barrier
as a critical regulator of leukocyte function and discuss how
host defense processes modulate epithelial homeostasis.
Key Words: epithelium • mucosa • host defense • innate • adaptive • network
INTRODUCTION
The last decades are highlighted by an increased incidence of
certain kinds of human pathologies including cancer, allergies,
inflammatory bowel disease (IBD), and autoimmune diseases [
1
].
Immune mechanisms are considered to play a central role in the
development of these diseases. Cancer is generally associated
with suppressed specific immunity, whereas allergies and autoimmune
conditions are characterized by pathologically activated Th2-
and Th1-mediated immune responses, respectively. Conversely,
all of these pathological conditions are characterized by persistent
tissue damage. There is a growing body of evidence indicating
that a key factor constituting a pathophysiological background
for these diseases is impaired communication between immune
and resident cells of tissues, where the pathological processes
develop.
Epithelial cells (ECs) cover the surfaces of the body such as skin, airways, and the intestinal tract and form the functional units of parenchymatous organs such as lungs, liver, pancreas, kidney, and many others. ECs provide an important link between the outside environment and the body interior. In pathological settings, epithelium can play different roles. It can serve as a portal of entry for microorganisms and harmful substances; an earliest sensor of different kinds of external danger including pathogens; a source of various signals, which constitute a disease-specific tissue microenvironment affecting the biology of many cells of the immune system; and a target of pathologic influences including those originating from different populations of leukocytes. Recent evidence strongly supports a central role of epithelial barrier function in the pathogenesis of IBD, asthma, interstitial lung diseases, cancer, and other pathological processes.
In this review, we summarize well-established and recent information about the interaction between ECs and leukocytes. Illustrative examples from different tissues, including thymus, skin, lung, intestine, and others, are used to demonstrate that ECs participate in regulation of virtually all immune-related processes, including development of lymphocytes, sensing, sampling of antigens in peripheral tissues and their presentation to T cells, and finally, regulation of the adaptive immune responses. Data are provided showing that leukocytes in turn are critically important for the maintenance of epithelial integrity.
EC—LEUKOCYTE CROSSTALK REGULATES IMMUNE HOMEOSTASIS
The epithelium provides a tissue barrier for virtually all kinds
of external danger. As a result of their proximity to the environment,
ECs of barrier organs such as the airways, the intestine, and
the skin can be viewed as a first line of host defense. Epithelial
barrier function is maintained by a well-organized polarity
so that apical surface faces the lumen or outside of the organ,
and basolateral surfaces are in continuous contact with the
body interior (
Fig. 1
). Apical surfaces of ECs contain cilia
necessary for cell motility and microvilli, which increase the
surface area important for transport of substances across the
membrane. The epithelium of the airways is covered by a surface
fluid comprised of a mucus layer and periciliary liquid contributing
together to the mucociliary escalator essential for the clearance
of microbes and other particles. Many antimicrobial substances
such as lactoferrin, lysozyme, defensins, and cathelicidins
accumulate in the airway mucus [
2
]. Under physiological conditions,
the airway epithelium inactivates bacteria and eliminates them
from the airways within several hours [
3
]. Epithelially derived
mouse ß-defensin-1 contributed to pulmonary host defense
[
4
]. Extensive framework of keratin filaments present in the
stratified squamous epithelium [
5
] and production of antimicrobial
peptides such as psoriasin and cathelicidin by keratinocytes
[
6
,
7
] contribute to an effective barrier function of the
skin. Epithelium-derived cathelicidin also protects the urinary
tract from bacteria [
8
].
The basolateral epithelial surface is characterized by different
kinds of connections between the cells. The most apically located
tight junctions (TJs) are comprised of special compounds such
as occludins, claudins, and zona occludens. These structures
separate the lumen from the tissue compartment and prevent paracellular
diffusion of fluids, electrolytes, macromolecules, and luminal
microorganisms [
9
]. This kind of barrier function can be compromised
by mucosal pathogens, which selectively attach to and disrupt
epithelial TJs [
10
]. It is interesting that the attachment
of the enterohaemorrhagic
Escherichia coli to intestinal epithelium
in vivo was found recently to be inflammation-independent [
11
],
suggesting that pathogen-induced damage to the epithelial barrier
might be responsible for initiation of the inflammatory process.
House dust-mite allergen
Dermatophagoides pteronyssinus has
been shown to open TJs as a result of its proteolytic activity,
allowing it to cross the epithelial barrier [
12
] and potentially
allowing its interaction with mucosal antigen-presenting cells
(APCs).
The defects in the epithelial barrier function are currently supposed to be responsible for the development of the chronic inflammatory events underling atopic dermatitis and asthma [13
, 14
]. For example, polymorphism in the gene encoding the serine protease inhibitor Kazal-Type 5 protein, which is involved in epithelial morphogenesis and repair, contributes to the risk of developing atopic dermatitis [15
]. Deficiency of this protein may result in recruitment of inflammatory cells in the dermis [16
]. Abrogation of the Jun proteins in epidermal keratinocytes resulted in a psoriasis-like skin disease [17
], again suggesting that defects in epithelial barrier may cause the local inflammatory process.
Another feature of polarized epithelium is adherens junctions localized subjacent to the TJs and required for structural integrity [18
]. E-cadherin, a major constituent of the adherens junctions in the epithelium, plays many roles in epithelial biology. First, it acts as a potent tumor suppressor by providing a firm adhesion between contacting ECs and preventing their migration and invasion of other tissues [19
]. Second, E-cadherin represents a target molecule for various pathogens. For example, it functions as a receptor for internalin, a surface protein of Listeria monocytogenes, required for entry of this intracellular pathogen into ECs [20
]. Finally, E-cadherin is an important adhesion point for different populations of 
Eß7 integrin (CD103)-expressing lymphocytes [21
]. Expression of the Eß7 integrin by a subset of regulatory T cells (Tregs) [22
] tempts to speculate that these cells can also attach to ECs.
Pattern-recognition receptors
It is now well established that ECs of many organs are able to sense the presence of microbes by using so-called pattern-recognition receptors (PRRs), including TLRs [23
], intracellular proteins of a nucleotide oligomerization domain (NOD) family, and probably other receptors [24
]. These sensor molecules recognize conserved molecular patterns characteristic for microorganisms, such as peptidoglycan (TLR2 in cooperation with TLR1 and TLR6, NOD1, and NOD2), LPS (TLR4), flagellin (TLR5), viral RNA (TLR7 and TLR8), and bacterial DNA (TLR9) [24
].
Although there is substantial evidence confirming the functionality of epithelial PRRs in vitro, it is currently unknown to which extent innate immune recognition by ECs contributes to induction of immune responses in vivo. The ability of ECs to provide a host defense response to invading pathogens independently on bone marrow-derived cells represents a controversial issue. It seems likely that EC-derived signals generated after PRR stimulation are necessary for activation of neighboring leukocytes, which in turn can govern the immunological process in a "professional" manner. In support of this theory, it has been documented recently that stimulation of epithelial TLRs in the intestine is necessary for the sampling of the luminal bacteria by mucosal DCs [25
] and regulates Ig class-switch recombination in mucosal B cells [26
]. In another study, the adoptive transfer of neo-self-specific CD8 cells resulted in the destruction of intestinal epithelium only after additional induction of nonspecific inflammatory signals by viral infection [27
]. Likewise, the development of the virus-induced autoimmune hepatitis was found to be dependent on the CXCL9 triggered in hepatocytes and other tissue cells in response to APC-derived Type I IFN and TNF- [28
]. In turn, CXCL9 attracted CXCR3+ self-reactive CD8+ T cells, which caused liver tissue destruction [28
]. Taking into account the observations that human hepatocytes can express TLR3 and Type I IFNs [29
], these cells might be able to play a role in local amplification of the autoimmune process.
Translocation of Igs
Translocation of Igs across the epithelial barrier represents an important mechanism of antigen sampling at the mucosal surfaces. Of note, this process is also dependent on the interaction between ECs and leukocytes. Dimeric IgA and pentameric IgM produced by the lamina propria B cells bind to the pIgR (also called trasmembrane secretory component), which is present at the basolateral side of the intestinal, respiratory, and urogenital epithelium and mediates transport of these Igs across ECs to the lumen [30
]. Luminal SIgA prevents adhesion and entry of antigens into the epithelium and plays many other protective roles in the mucosa [31
]. An in vivo study revealed that pIgR-mediated secretion of IgA is important for the maintenance of epithelial barrier function [32
]. IgG can be transported across intact barriers such as placenta and polarized intestinal and respiratory epithelia using neonatal FcR (FcRn) expressed by ECs [33
]. In contrast to the pIgR-mediated IgA delivery, the transport of IgG can occur in both directions, enabling the export of IgG to the mucosal surface and the retrieval of luminal antigen-IgG complexes into the mucosa [34
]. This mechanism of the EC-leukocyte crosstalk is likely important for the mucosal protection in vivo. In a recent study, FcRn-deficient mice were susceptible to infection with an epithelium-specific pathogen Citrobacter rodentium [35
]. SIgA can also be transported from the intestinal lumen to underlying, organized lymphoid tissues using a specialized EC present in the gut mucosa [36
].
EC—leukocyte connections within tissues
Within mucosal organs and in the skin, ECs are in close contact with a variety of innate and adaptive immune cells. The mucosa of many barrier organs, including the gut, pharynx, larynx, eye conjunctiva, Eustachian tube, lacrimal, and salivary glands, is equipped with the aggregates of lymphocytes called MALT. It is important that immune cells within MALT acquire antigens via an EC-mediated mechanism and are thought to operate partly independently from the systemic immunity under the control of the tissue microenvironment. Apart from MALT formations, numerous DCs and lymphocytes reside within the healthy epithelium and subepithelial areas. These tissue compartments can also be populated by other resident and recruited cell types involved in inflammation and immunity, such as macrophages and granulocytes. This close vicinity together with the capability of the involved cells to secrete abundant mediators determine the character of immune responses in peripheral tissues.
EC—MALT connection
As a result of close anatomical and functional relationships with a special kind of EC—"follicle-associated epithelium" (FAE)—induction of immune responses in the MALT is coupled immediately to uptake of the luminal antigens [37
]. This uptake is mediated by "microfold" or membranous (M) cells, a specialized population of ECs present in the FAE, which overlies the subepithelial lymphoid follicles in the gastrointestinal and respiratory tracts [38
]. An important feature of M cell-mediated sampling of antigens is that microbes taken up by these cells are then delivered directly to intraepithelial lymphoid cells, subepithelial areas, and underlying lymphoid follicles containing DCs, T and B cells. This close intercellular collaboration is determined by a unique structure of M cells: a deep invagination of the basolateral surface forms a so-called intraepithelial "pocket" into which lymphocytes migrate and where different populations of intraepithelial leukocytes reside [39
].
Many pathogens including Type I reovirus, poliovirus, and invasive bacteria such as Salmonella, Shigella, and Vibrio species use M cells as a portal of entry into the body to establish infection [40
] and initiate protective immune responses. M cell-mediated delivery of Mycobacterium tuberculosis from the airway lumen to the lung intraepithelial leukocytes and the lymph nodes draining the respiratory tree is supposed to contribute to rapid activation of protective pulmonary immune responses [41
].
In addition, M cells express an IgA-specific receptor on their apical surfaces, which mediates the transport of SIgA from the intestinal lumen to underlying gut-associated, organized lymphoid tissues [36
], where SIgA can be internalized by DCs in the subepithelial dome region [42
]. Uptake of IgA-opsonized, commensal microorganisms is supposed to play a role in the maintenance of immune homeostasis in the intestine [43
]. Subsequently, it has been shown that mucosal DCs carrying commensal bacteria selectively induce local IgA production [44
].
Different factors expressed by ECs can contribute to the compartmentalization of leukocytes within mucosa. For example, FAE of the Peyer’s patches produces chemokines CCL20 and CCL9 implicated in the recruitment of DCs toward the mucosal surfaces [45
, 46
]. EC-derived CCL20 is believed to play a role in homeostatic recruitment of B cells into the mucosa and local lymphorganogenesis [47
]. IL-7 constitutively produced by ECs is implicated in the formation of the Peyer’s patches [48
, 49
]. The mucosal epithelial chemokine/CCL28 is implicated in a directed migration of IgA+ plasmablasts and plasma cells to many mucosal organs including the salivary glands, tonsils, intestine, and appendix [50
]. There is evidence that this chemokine is up-regulated in the mammary gland during lactation and is responsible for the local accumulation of IgA-secreting plasma cells, contributing to an appropriate transfer of IgA from mother to infants [51
].
Subepithelial DCs can capture bacteria, which enter via M cells, and as a consequence, migrate to adjacent T cell zones [52
], where DC maturation, antigen presentation, and finally, T cell activation [53
] occur. In a recent study, sensing of pathogen-associated patterns by FAE cells via TLRs resulted in an increased M cell-mediated uptake of microparticles and subsequent migration of DCs in the epithelium [54
]. This demonstrates that antigen acquisition and induction of immune responses within mucosa involve a complex, multistep process dependent on the coordinated interaction between different cell types.
EC—DC
It is evident that initiation and control of immunological process within mucosal tissues are dependent on interaction between ECs and DCs. Both cell types are involved in sensing and sampling of antigens. By producing a plethora of mediators, ECs are able to modulate the status of the DCs substantially under the steady-state and inflammatory conditions. In the skin, respiratory tract, oral cavity, vagina, and many other barrier organs and in the intestine outside the organized MALT, sampling of pathogens usually occurs via M cell-independent mechanisms [55
]. Lamina propria and intraepithelial DCs (IEDCs) contribute to this process.
DCs have been found to exist within the epithelium of different organs, including skin [56
], airways [57
], tonsils [58
], and vagina [59
]. Such a close neighborhood per se strongly suggests an extensive EC-DC cooperation. Although the origin of the IEDCs remains largely obscure, the local epithelial microenvironment may serve as a niche for the development and homeostatic maintenance of these cells. Diverse EC-derived factors are believed to contribute to these processes. This is perhaps exemplified best by the local regulation of Langerhans cells (LCs), the only DCs of the epidermis. GM-CSF, produced by keratinocytes, plays a role in survival of the LCs [60
], the chemokine CXCL14, which is constitutively produced in healthy skin, attracts CD14+ DC blood precursors to epidermis for their intraepithelial positioning, where they differentiate into LC-like cells [61
]. In the vagina, recruitment of LC precursors is supposed to be mediated by CCL20 secreted by vaginal ECs [62
]. Intraepidermal differentiation of LCs may be mediated by a complex of factors including Notch ligand Delta-1 and GM-CSF expressed in the skin [63
]. Whereas the monocytes appear to be direct precursors of LCs in vivo during inflammation [64
], under steady-state conditions, LCs are likely able to be maintained locally [65
]. This supports the role for ECs in providing a homeostatic niche for IEDCs. The biology of IEDCs present in other organs is less understood, and their general role in the induction of immune responses remains unclear. One interesting study exists, indicating the possibility of a direct interaction between DCs and lymphocytes within the intestinal epithelial compartment [66
].
It is generally accepted that normal, epithelial environments exert a suppressive effect on DCs, thereby preventing unwanted, immune activation. For example, the ligation of E-cadherin on LCs as a result of their interaction with E-cadherin-expressing keratinocytes [67
] can potentially inhibit their maturation [68
], providing a mechanistic explanation for the immature phenotype of steady-state LCs. In the intestine, colon ECs inhibit a steady-state maturation of local DCs via production of TSLP [69
] and probably other mediators, explaining the immature phenotype of mucosal DCs. Moreover, TSLP-"educated" DCs were not able to prime Th1 responses in response to Salmonella [69
]. Instead, a Th2-priming capacity of airway [70
] and colon epithelium-associated or epithelium-educated DCs [69
] has been described. In addition to TSLP, whose Th2-promoting potential was determined in several studies [69
, 71
, 72
], other epithelial factors, including GM-CSF [70
, 73
] and PGE2 [74
], may educate DCs, resulting in a phenotype that supports development of Th2 responses. Increased expression of GM-CSF by asthmatic airway epithelium [75
] and by keratinocytes in atopic dermatitis may explain the increased number and sustained activation of DCs in the target organs of patients with Th2-mediated diseases [76
]. LL-37/human cathelicidin antimicrobial peptide 18 (hCAP-18), the human antimicrobial peptide of the cathelicidin family, which is normally expressed in epithelia of various organs [77
] and neutrophils [78
, 79
], modulates the phenotype and function of DCs [80
, 81
]. Identification of LL-37/hCAP-18 expression by DCs [82
] and recent findings that LL-37 modulate epithelial responses, which are described below, indicate that LL-37 might mediate interactions between ECs and DCs. Also ß-defensins are implicated in the chemoattraction of immune cells such as DCs [83
].
During inflammation, ECs are the principal source of the chemokine CCL20 necessary for attracting immature DCs, which usually express CCR6 [84
]. Before the discovery of this chemotactic mechanism, it has been reported that DCs migrate rapidly toward epithelium during acute infection [85
]. In the gut, this chemokine is induced in intestinal ECs after their activation with flagellin [86
]. The similar mechanism might be used by airway ECs upon their exposure to allergens [87
] and ambient particulate matter [88
]. Tubular ECs of the transplanted kidney overexpress CCL20 [89
] and therefore, might contribute to DC recruitment during the allograft rejection. Increased levels of CCL20 have been found in the primary colonic epithelium of IBD patients [90
] and in the epidermis of patients with atopic dermatitis [91
]. Consistently, expression of the CCR6, which is a receptor for CCL20, was necessary to establish allergic pulmonary inflammation in mice [92
].
Direct sampling of luminal pathogens by DCs represents a potentially relevant mechanism of antigen acquisition in mucosal surfaces. DCs express classical TJ proteins and form temporal junctions with ECs, allowing them to extend their dendrites between ECs without compromising epithelial integrity [93
]. Also in the lung, a subset of IEDCs extends their processes into the airway lumen [94
]. Proteolytic cleavage of TJs may represent an alternative mechanism. As already mentioned, D. pteronyssinus, one of the major allergens of the house dust mite, has cysteine proteinase activity able to cleave the TJ protein occludin and allow access to DCs [12
]. Consistently, DCs were found to penetrate the nasal epithelial layer in patients with allergic rhinitis but not in healthy subjects [95
]. Factors produced by activated ECs seem to play an important role in the induction of transepithelial DC processes. It has been shown in vivo that interaction between fractalkine produced by intestinal ECs and its receptor CXCR1 expressed on mucosal DCs has a critical role in formation of transepithelial dendrites [96
]. A more recent study revealed that recognition of microbial products by epithelial TLR is also necessary for this process [25
]. Taking into account that epithelial TLR function [23
] and fractalkine expression [97
] can be augmented substantially by inflammatory mediators, increased contact of mucosal DCs with luminal content can theoretically underlie persistent immune activation characteristic for chronic mucosal pathology in IBDs and other inflammatory diseases.
The intimate crosstalk between ECs and mucosal DCs is thought to be exploited by the HIV [98
], which can be transported across the epithelium and delivered to DCs and macrophages by M cells without causing damage to the epithelial barrier. Indeed, there is evidence that the transepithelial transport of HIV-1 is mediated by M cells [99
]. An interesting chemotactic mechanism for selective DC migration into the site of potential entry of the virus has been described recently, in which vaginal ECs respond to factors present in the semen by secreting CCL20 and thereby, promoting the recruitment of the LC precursors [100
].
EC—lymphocyte
Probably the most prominent example for interaction between the epithelium and leukocytes is the development of T lymphocytes in the thymus, where self-tolerant T cells bearing ß forms of the TCR differentiate under strict control of so-called "thymic microenvironment" constituted by a network of thymic ECs (TECs) [101
]. Cortical TECs provide a diverse array of signals (MHC class II molecules, cytokines, growth factors, Notch ligands, and probably others) for attraction of early lymphoid precursors and positive selection of thymocytes. In the medulla, thymocytes mature into CD4+ or CD8+ single-positive cells, and autoreactive T cell clones are eliminated. Medullary TECs express the antigens characteristic for ECs of different organs, thereby contributing to the establishment of self-tolerance, probably necessary for preventing organ-specific autoimmunity [102
]. The development of CD4+CD25+ Tregs in human thymus has been shown to be mediated by a crosstalk between medullar ECs and DCs: Hassall’s corpuscles, a group of ECs residing within the thymic medulla, were found to express TSLP, which educated DCs to induce CD4+CD25+ Tregs [103
]. Thus, the prototypical roles of the thymic epithelium are compartmentalization, instruction, and regional specialization. These epithelial functions can also be found in other organs.
The epithelium of the small intestine [104
], lungs [105
], skin [106
], and other organs contains abundant IELs, a heterogeneous population of cells scattered along the length of the basolateral epithelial surface. IELs are mostly T cells [107
]; however, the population of CD3-negative cells with NK cell features has also been revealed in the epithelium [108
]. IELs differ from the lymphocytes of other compartments in that they express mainly monospecific or oligoclonal TCRs, express Eß7-integrin, allowing their retention within epithelium [21
], and constitutively display a phenotype of activated effector/memory cells [107
, 109
]. IELs display a high cytotoxic activity [110
], which is believed to be acquired under the influence of the epithelial microenvironment [111
].
The ß TCR-expressing IELs usually represent memory T cells, which were activated first within the lymphoid tissues and eventually migrated into the target epithelium under the influence of chemotactic factors of epithelial origin. For example, in the gut, T cells populate the small intestinal epithelium in response to CCL25, which is produced by ECs [112
]. Many other epithelial chemokines, including CCL28 [113
] and fractalkine [97
], are implicated in the recruitment of T cells into the epithelium. During inflammation, ECs attract not only effector cells but also the cells with regulatory activity. As recently demonstrated, a subset of Tregs accumulated within inflamed human liver expressed CCR10, a receptor for CCL28, which in this study was produced by ECs of the bile ducts [114
]. These are only a few from numerous examples showing the capability of ECs to coordinate protective/cytotoxic and regulatory branches of the immune system.
In contrast to the ß TCR+ IELs, the so-called "natural memory T cells" expressing the 
TCR reside permanently within epithelial tissues [109
]. It has been reported that the population size of a major subset of T cells can be maintained in athymic mice also lacking lymph nodes, Peyer’s patches, and isolated lymphoid follicles [115
]. Although there are studies supporting the essential role for thymus in the development of TCR-expressing cells [116
], the data from athymic mice indicate that these cells possibly differentiate and mature within the epithelium.
A growing body of evidence highlights that ECs can influence the maintenance and function of IELs by means of soluble factors and contact interactions. The most important soluble epithelial factors regulating the functional status of the mucosal lymphocytes are IL-7 and IL-15. EC-derived IL-7 is important for the development of T cells [49
] and memory CD4+ T cells [117
] and for the homeostatic proliferation of CD8+ T cells [118
]. In vivo data show that increased expansion of the memory CD4+ mucosal T cells by IL-7 may underlie inflammatory pathology in chronic colitis [119
]. Epithelial IL-15 plays important roles in proliferation and maintenance of IELs [120
] and is implicated in the pathogenesis of mucosal damage in IBD [121
] and celiac disease [122
]. IL-15 production by intestinal ECs and consequently, IL-15-mediated IEL homeostasis may be dependent on recognition of microbial factors by TLRs. In mice that lack MyD88, an adaptor essential for signaling via most of the TLRs, the size of the IEL population is reduced severely in parallel with a decrease of IL-15 expression in ECs [123
]. It is important that introduction of the exogenous IL-15 into these mice was sufficient to restore the numbers of IELs [123
]. In a similar manner, keratinocyte-derived IL-7 and TNF- promote the growth of dendritic epidermal T cells, a unique subset of T cells populating the epidermis in mice [124
]. Constitutive exposure to EC-derived homeostatic cytokines may, at least in part, explain the unique ability of IELs to survive within the epithelium for at least several months, as it has been demonstrated in the lung [125
]. Conversely, persistent stimulation of lymphocytes with these cytokines may have a pathological character in Sézary disease [126
, 127
], a cutaneous T cell lymphoma in which CD4+ T cells increase in skin to large numbers.
Contact interaction with the neighboring ECs may provide positive and negative signals for lymphocyte survival and activation. It is suggested for a long time that ECs can induce immune responses as a result of their ability to sample, process, and present antigens to T cells directly [128
129
130
]. MHC class I and class II molecules, as well as an array of diverse, nonclassical MHC class I molecules, such as the MHC class I chain-related gene A (MICA) and B (MICB), C1d, and FcRn, can be expressed by ECs of different organs [131
]. Some unknown EC membrane factors may suppress the proliferative response of IELs stimulated via the TCR-CD3 complex [132
]. In a recent study, antigen expressed exclusively in enterocytes directly induced CD4+ T cells with a regulatory phenotype in a transgenic autoimmune model [133
]. However, there is no direct evidence that ECs can function as APCs in vivo.
In addition, ECs express some other molecules mediating their contact interactions with lymphocytes, including the costimulatory molecules CD80 and CD86 [134
], novel B7 family member ICOS ligand and programmed death-1 ligand [135
], CD40 ligand [136
], and some others. Although the physiological relevance of the expression of such molecules is largely obscure, there is some evidence that they might play detrimental and protective roles in the immunopathogenesis of chronic inflammatory diseases. Experimental overexpression of CD40 in keratinocytes resulted in chronic dermatitis and systemic autoimmunity [137
], whereas the receptor activator of NF-
B ligand, which was detected in psoriatic but not healthy epidermis, induced systemic expansion of Tregs via activation of LCs [138
].
There is a correlation between the numbers of epithelial tumor-infiltrating lymphocytes and an improved clinical outcome in human malignancies including colorectal [139
, 140
], ovarian [141
], esophageal [142
], rectal [143
], gastric [144
], and other epithelial cancers, reflecting the capability of IELs to recognize tumor-associated antigens expressed on nascent transformed ECs and subsequently destroy the latter. Increased expression of MICA in epithelial cancers [145
] can contribute to NK cell-mediated lysis of cancer cells [146
]. In colon carcinoma, the heat shock protein 96 derived from tumor cells acts as a chaperone of antigenic peptides to CD8+ T cells, resulting in activation of the latter [147
].
However, diverse factors produced by cancerous cells can suppress anti-tumor immunity substantially [148
]. It has been found recently that MICA expression by tumor cells, previously thought to be exclusively beneficial, can reduce the expression of its receptor on tumor-infiltrating lymphocytes [149
] and mediate a suppressive effect on T cell proliferation [150
]. Overexpression of IL-23 by carcinoma cells can account for the failure of protective cytotoxic CD8 T cells to infiltrate tumors [151
]. By producing the chemokine CCL22, epithelial ovarian cancer cells attracted CD4+CD25+ Tregs [152
], which are potent inhibitors of protective immune responses. Indeed, an increased proportion of Tregs has been observed within epithelial tumors [153
, 154
]. The suppressive effect of tumors on T cell immunity can be mediated via DCs. Thus, vascular endothelial growth factor (VEGF) produced by tumor cells inhibits functional maturation of DCs [155
].
EC—granulocytes, monocytes, macrophages, and mast cells
Interaction of ECs with bone marrow-derived host defense cells is essential for the development and control of inflammatory responses. Epithelial proinflammatory factors are usually induced in response to tissue injury or recognition of microbial patterns via PRRs [156
]. It is important that invasive pathogens induce release of inflammatory cytokines from ECs much stronger than noninvasive microbes [157
158
], once again stressing the role of epithelial barrier integrity in regulating inflammation.
The earliest cells accumulating in damaged or infected tissues are neutrophils, which are usually recruited by tissue-derived IL-8, a cytokine released abundantly from ECs of various organs after damage and activation by pathogens or inflammatory mediators [157
, 159
160
161
]. During allergic response, the predominantly recruited granulocytes are eosinophils. The ability of ECs to produce eotaxin, the major chemoattractant for eosinophils, is well established [160
]. Another important eosinophil chemoattractant, RANTES, can be secreted from airway ECs infected with respiratory syncytial virus [163
].
As a result of their cytotoxic activity, however, granulocytes can cause damage not only to microbial but also to tissue structural cells. For example, enhanced neutrophil activity is an important factor of epithelial destruction in acute lung injury [164
]. It is important that neutrophils adhere stronger to hypoxic epithelia, as the latter express increased levels of adhesion molecules [165
]. This may be relevant for airway inflammation in cystic fibrosis (CF) lung disease, which is characterized by a primary defect in EC function, tissue hypoxia, and neutrophil-mediated tissue damage. Indeed, an increased adhesion of neutrophils to CF epithelia associated with inflammation has been reported [166
]. Recently, increased numbers of neutrophils have been detected in the distal airway epithelium of patients with chronic obstructive pulmonary disease [167
].
In addition to direct cytotoxicity, granulocytes can alter some host defense functions of ECs. Neutrophil elastase can induce expression of IL-8 [168
], mucins [169
], epithelial antimicrobial substances such as secretory leukocyte peptidase inhibitor, and human ß-defensin 2 [170
] in ECs, providing a self-amplifying defense mechanism. In a recent study, the neutrophil-derived defensins increased the expression of surface molecules on lung ECs and CD4+ T cells necessary for their initial cognate interaction [171
]. Eosinophil-derived cationic peptides can activate ECs to produce growth factor-like molecules, matrix metalloproteinases (MMPs), and other factors involved in tissue remodeling processes [172
]. Although transepithelial migration of neutrophils has been implicated in pathogenesis of mucosal damage in IBD [173
], luminal entry of granulocytes may also contribute to the resolution of inflammation through the removal of cytotoxic cells from tissues [174
]. In hypoxic tissues, such a protective mechanism may operate via the hypoxia-inducible CD55 on the apical membranes of ECs, which mediates clearance of neutrophils from the epithelial surface [175
].
Monocytes can be recruited into inflamed tissues under the influence of a different set of chemokines, including MCP-1, which can be secreted by ECs [176
]. Injured or infected ECs produce IL-6, another cytokine-mediating monocyte chemotaxis [177
]. Prolonged secretion of IL-6 by tissue cells, including hepatocytes, keratinocytes, and other ECs as a result of persistent tissue injury is currently thought to be critical for the maintenance of chronic inflammation [177
, 178
]. Lung alveolar ECs infected with influenza A virus release chemokine CCL2, which together with a set of adhesion molecules expressed by ECs, mediates transepithelial migration of monocytes [179
]. The last observation demonstrates that in addition to recruiting inflammatory cells into the site of the pathogen entry, ECs provide molecular clues guiding their migration within mucosal tissues. Other cytokines, including IL-1ß and TNF-, whose production by ECs can be up-regulated in inflammatory settings [157
, 180
], are well-known activators of monocyte and macrophage functions. The ability of ECs to produce GM-CSF necessary for the differentiation and survival of monocytes and macrophages was mentioned above.
Similar to the local education of DCs by epithelial factors, tissue-specific microenvironments may play an important, instructive role in shaping the phenotype and function of macrophages, which differentiate from monocytes and reside within tissues. Alveolar macrophages (AMs) are believed to possess some immunoregulatory properties [181
], in contrast to their highly proinflammatory intramucosal counterparts. Recently, it has been demonstrated that constitutive expression of vß6 integrin by alveolar ECs is indispensable for continuous, steady-state activation of epithelial TGF-ß [182
], which in turn is necessary for the tonic inhibition of AMs. Following microbial stimulation via TLRs, AMs initiate down-regulation of this integrin expression in ECs, thereby escaping from epithelial control [183
]. In the intestine, EC-derived TGF-ß dictates the noninflammatory phenotype of mucosal macrophages, which do not express CD14, CD16, CD11b/CD18, CD11c/CD18, and other surface molecules necessary for sensitivity to microbial and immune stimulation and maintain their phagocytic and bactericidal activity against pathogens [184
]. It should be noted that cytokines TNF- and IL-1ß, released from activated macrophages, can modify the host defense potential of ECs dramatically by increasing their production of proinflammatory cytokines [176
, 185
] and antimicrobial peptides [186
], as well as inducing expression of TLRs [187
] and costimulatory molecules [131
] on ECs. Under influence of TNF- and IL-1ß, human lung [188
] and renal ECs [189
] are able to produce considerable amounts of long pentraxin 3 (PTX3), a newly discovered soluble PRR playing a critical role in host defense, as demonstrated recently in experimental models of lung infection caused by Aspergillus fumigatus and Pseudomonas aeruginosa [190
]. However, overexpression of PTX3 in ECs is suggested to mediate inflammatory tissue damage in acute lung injury [191
], tempting to speculate that this protein might provide a molecular link between ECs and inflammatory cells.
Although mast cell (MC) infiltration of the bronchial epithelium has been considered as an asthma-specific pathological event [192
], in vitro evidence indicates that human lung MCs can also adhere to normal airway epithelium [193
]. Such close relationships might influence the biology of both cell types. Indeed, recent studies show that human airway epithelium can inhibit MC degranulation [194
] and support their survival [195
], suggesting that MCs can also be a subject of epithelial education. Acquisition of inflammatory features by mucosal MCs may require Th2 cytokines [195
] or some additional priming signal from ECs. In support of the latter theory, TSLP derived from keratinocytes upon infection or mechanical injury has been reported to activate MCs in the skin [196
]. MCs can also modulate epithelial responses. Histamine released from activated MCs can promote proinflammatory responses in keratinocytes [197
]. It is interesting that amphiregulin, a ligand for the epidermal growth factor (EGF) receptor, can be produced by activated MCs and increase mucin gene expression in the airway ECs [198
].
EC—LEUKOCYTE CROSSTALK REGULATES TISSUE HOMEOSTASIS
Not only do leukocytes receive EC-derived signals, they also
play a critical role in the regulation of epithelial homeostasis.
As mentioned above, the thymus serves as a valuable model of
bidirectional interactions between ECs and leukocytes. Differentiation
of thymic epithelia is dependent on the presence of thymocytes,
as the absence of TCR-expressing cells resulted in defective
development of the medullary TECs [
199
]. T cell progenitors
are likely necessary for the formation of the cortex epithelium
[
200
], whereas differentiation of medullary TECs requires lymphotoxin
ß expressed by thymocytes and its receptor expressed
by immature TECs [
201
]. The latter signal is likely critical
for the expression of the transcription factor autoimmune regulator,
responsible for the ectopic expression of peripheral tissue
antigens in medullary TECs [
202
].
Leukocytes play an equally important role for the development, structural integrity, and function of the epithelium of other organs. Under the influence of the locally produced CSF and eotaxin, macrophages and eosinophils home to the developing mammary gland, where they play a nondispensable role for the epithelial ductal outgrowth [203
]. In a similar manner, macrophages contribute to the development of the islet cell populations in the pancreas [204
]. Given that in the adult human pancreas, the ß cell can originate from the nonendocrine ECs [205
], macrophages might act as regulators of ß cell differentiation with important clinical consequences for diabetes. Factors present in or produced by the immune cells of mucosal lymphoid follicles play a role in the generation of M cells from the cells of FAE [206
207
208
], and mature B cells are required for the formation of a full-sized FAE in vivo [209
210
]. However, B lymphocytes have been found to suppress the generation and differentiation of the intestinal villous epithelium under the homeostatic conditions [211
].
Being in a state of continuous interaction with ECs, IELs play a particularly important role in the establishment and maintenance of epithelial integrity. Thus, local T cells are necessary for the differentiation and maintenance of intestinal crypt epithelia [212
] and protection of keratinocytes from apoptosis [213
]. The ability of these cells to recognize molecules expressed by the damaged ECs [214
] and secrete growth factors, including the IGF-1 [213
] and members of the KGF family [215
, 216
], is implicated in the epithelial repair process in skin and intestine. During infection, IELs can maintain the integrity of epithelial TJs [217
].
It is known from the time of Mechnikov [218
] that tissue injury results in a rapid recruitment of the cells with host defense properties. Wound healing is regulated by different populations of leukocytes, including neutrophils, monocytes/macrophages, lymphocytes, and MCs, which accumulate within the wound and possess a substantial capacity to modulate the repair processes. The recruitment of these cells from circulation is dependent on chemokines produced by tissues following injury. As mentioned in a previous section, IL-8 and MCP-1 are critical for the recruitment of neutrophils and monocytes, respectively [219
]. Although being necessary for effective clearance of pathogenic bacteria, neutrophils accumulated within the damaged area exert a rather detrimental effect on epithelial integrity [220
]. In vivo neutrophil depletion increased the migration of keratinocytes and accelerated cutaneous wound-closure [221
]. Macrophages produce several growth factors potentially important for epithelial repair [222
]. Recently, it has been shown that macrophages activated via the TLR-MyD88 pathway contribute to repair of the damaged intestinal mucosa by inducing a regenerative response in epithelial progenitor cells [223
]. Leukocytes sensing microbes after disruption of epithelial barrier are important for creating a PGE2-rich microenvironment, supporting the compensatory proliferation of colonic epithelial progenitors [224
]. This is consistent with the earlier observation that MyD88-mediated signaling induced following innate immune recognition of commensal flora in the intestinal mucosa is important for the maintenance of epithelial integrity [225
].
Antimicrobial peptides are effector molecules of the innate immune system and produced by ECs and leukocytes. In addition to their direct, antimicrobial activity, several antimicrobial peptides regulate immune mechanisms or cellular processes. Already mentioned human cathelicidin LL-37/hCAP-18 has been reported to induce chemotaxis of neutrophils, monocytes, and T cells [226
] and also stimulates epithelial wound closure [227
, 228
]. The human neutrophil peptides or -defensins can also modulate epithelial homeostasis by increasing EC migration, proliferation, and mucin gene expression [229
].
Interaction between ECs and leukocytes in cancer development
Cancer is often of epithelial origin. Many conditions, which are associated with cancer development, are characterized by a damaged epithelial barrier, as demonstrated for colitis-associated colon cancer and lung carcinomas [230
]. Inflammatory and immune processes can promote epithelial cancer development [231
, 232
]. Increased numbers of different types of leukocytes have been found to infiltrate many tumors being associated with poorer clinical outcomes [233
]. Tumor-associated macrophages (TAMs) are the best-characterized tumor-promoting cells linking chronic inflammation and cancer [234
]. It is important that tumor cells are responsible for recruitment and pathological conditioning of TAMs [235
].
Interaction between the epithelial tumor cells and tumor-infiltrating inflammatory cells can be mediated by virtue of various cytokines. TNF-, also called "tumor-promoting factor" [236
], can be produced by the malignant tissue and TAMs and increase survival, proliferation, migration, and invasiveness of epithelial cancer cells, as well as further amplify the inflammatory process within tumors [236
]. Overproduction of IL-1ß during Helicobacter pylori infection may result in inflammatory mucosal damage and subsequent development of gastric cancer [237
]. The relevance of CSF-1 released by the breast and ovarian epithelial cancer cells and serving as a major attractant of macrophages into these tumors, can be supported by the fact that in CSF-1-knockout mice, the rate of tumor progression is reduced substantially [238
]. Macrophages expressing EGF promote migration and invasiveness of breast carcinoma cells as well as CSF-1 expression by the latter, and cancer cell-derived CSF-1 is able to induce EGF production in macrophages [239
]. Animal models of colitis-associated cancer show the dependency of cancer growth on myeloid cells [240
]. Although epithelial NF-B activation has been shown to correlate directly with carcinoma incidence, NF-B in myeloid cells is considered to be essential for epithelial tumor progression [240
]. In addition, there is evidence that hypoxic tumor tissues attract monocytes, stimulate their in situ differentiation into TAMs, and prime their tumor-promoting activities [241
]. In a recent study, targeted reduction of TAM numbers in models of breast, lung, and colon carcinomas resulted in a substantial suppression of tumor growth and metastasis and a marked decrease of TAM-associated mediators TNF-, MMP-9, TGF-ß, and VEGF [242
].
Neutrophils are implicated in the development of alveolitis in the bronchioalveolar subtype of lung adenocarcinoma and, thus, contribute to the progression of this inflammation-associated cancer [243
]. Within the tumor, neutrophils may be a source of growth factors [244
]. MCs can also contribute to carcinogenesis, as MC-deficient mice, in which epithelial carcinogenesis has been initiated by introduction of oncogenes from the human papillomavirus Type 16 in keratinocytes of the cervix and skin, displayed an attenuated neoplastic development accompanied with a decreased proliferation of keratinocytes, as compared with the wild-type mice [245
]. MMP-9 expressed by various inflammatory cells, including macrophages, neutrophils, and MCs, is currently implicated in the oncogene-induced keratinocyte hyperproliferation [246
].
Also, adaptive immune mechanisms can support epithelial tumor growth. There is evidence that CD4+ T cells, infiltrating dysplastic skin lesions and activated there by Staphylococci colonizing neoplastic epidermis extensively, promote skin carcinogenesis [247
]. Reduced tumor invasion and metastasis have been observed in mice lacking B cells [248
]. A more recent study provides evidence that soluble B cell-derived factors play an important role in the promotion of early epithelial carcinogenesis via induction of a proinflammatory environment rich in granulocytes and MCs [249
].
CONCLUSION
ECs and leukocytes form a complex network, which regulates processes
such as host defense, inflammation, organogenesis, tissue repair,
cancer growth, and immunity. Bidirectional interactions rather
than functions of individual cell types contribute to the maintenance
of tissue integrity and immune homeostasis under steady-state
and determine a complex pathologic tissue microenvironment during
the development of diseases (
Fig. 2
). The cell types involved
fulfill specialized tasks within this network. Professional
immune cells have low thresholds in the detection of microbes
and their patterns. These cells are essential for the specific
recognition of antigens, establishment of adaptive immune responses,
and inflammation-dependent elimination of pathogens. However,
there should be mechanisms capable of controlling the abundance
of potentially harmful immune inducers and effectors. One of
the most critical functions of ECs is to separate the inside
from the outside and to protect the sensitive immune system
from continuous contact with external microorganisms. The instructive
role of the epithelium includes two basic mechanisms: education
of tissue leukocytes by supporting their survival but limiting
their inflammatory and immunogenic activities under the steady-state
(Fig. 2A)
and priming of resident immune cells and leukocytes
from distant compartments to establish local inflammation and,
in certain cases, immune responses necessary for the elimination
of pathogens, which crossed the barrier
(Fig. 2B)
. Dysregulation
of these processes forms a pathophysiological basis for chronic
diseases, associated with uncontrolled inflammation, tissue
injury, and inappropriate repair. Persistent inflammation and
immune activation may result in tissue remodeling, as in the
case of fibrosis, or may promote epithelial carcinogenesis
(Fig. 2C)
.
The networks described here are involved in virtually all diseases,
which take place at body surfaces. Also, the maintenance of
homeostasis critically depends on these interactions. The concept
of a functional network between ECs and leukocytes should allow
the development of strategies to identify target molecular and
cellular mechanisms, which are critically involved in EC-leukocyte
interactions during disease development.
ACKNOWLEDGEMENTS
The Deutsche Forschungsgemeinschaft, the Bundesministerium für
Bildung und Forschung, the Kempkes-Stiftung, and the Deutsche
Herzstiftung funded work in the authors’ laboratory.
Received February 7, 2007;
revised April 1, 2007;
accepted April 1, 2007.
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ABSTRACT
INTRODUCTION
