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Dendritic Cells in Chronic Obstructive Pulmonary Disease

New Players in an Old Game

¹ Lung Pathology, Department of Gene Therapy, Imperial College London, London, United Kingdom; and ² Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium

Correspondence and requests for reprints should be addressed to Prof. Peter K. Jeffery, F.R.C.Path. D.Sc., Lung Pathology Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. E-mail: p.jeffery{at}imperial.ac.uk

ABSTRACT

Dendritic cells (DCs) are professional antigen-presenting cells responsible for immune homeostasis. In the lung's responses to tissue damage or infection, they initiate and orchestrate innate and adaptive immunity. There are immature and mature states and at least three phenotypic and functional subsets. DCs circulate in the blood and localize to mucosal surfaces in immature form where they act as sentinels, sampling constituents of the external environment that breach the epithelium. With internalization of antigen, they are activated, mature, and migrate to draining lymph nodes to induce the proliferation and regulate the balance of Th1/Th2 T cells or to induce a state of tolerance, the last dependent on maturation status, extent of cell surface costimulatory molecule expression, and cytokine release. Cigarette smoke has modulatory effects varying with species, dose, the location examined within the lung, and the marker or technique used to identify DCs. Healthy smokers (and smokers with asthma) have reduced numbers of large airway mature DCs. In chronic obstructive pulmonary disease, the number of immature DCs is increased in small airways, whereas in smokers with chronic obstructive pulmonary disease, the total number of DCs appears to be reduced in large airways. We hypothesize that the long-term effects of cigarette smoke include reduction of DC maturation and function, changes that favor repeated infection, increased exacerbation frequency, and the altered (CD8⁺ T-cell predominant) pattern of inflammation associated with this progressive chronic disease.

Key Words: dendritic cells • chronic obstructive pulmonary disease • smoking

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide. Its definition recognizes the "abnormal" exaggerated or amplified inflammatory response to cigarette smoking. The pattern of inflammation involves lymphocytes, macrophages, and, when severe or in association with exacerbations, neutrophils (1–3). Cells of innate immunity, such as neutrophils and macrophages, are normal responders to tissue damage and oxidative stress induced by cigarette smoke (CS), but it remains unclear why cells of adaptive immunity, particularly lymphocytes of the CD8⁺ phenotype, accumulate in the lungs of smokers with COPD. Moreover, organization of the recruited lymphocytes into lymphoid follicles and the presence of oligoclonal lymphocytes indicate that lymphocyte recruitment is the result of a targeted, antigen-specific adaptive immune response, rather than of nonspecific trafficking of lymphocytes to the lung (3–5).

Such lymphocyte activation usually requires the assistance of antigen-presenting cells (APCs) that recognize, process, and present the processed antigen to naive lymphocytes (6). Dendritic cells (DCs) are potent APCs designed to initiate primary immune responses. They are recruited from the circulation and migrate toward epithelial surfaces, where they capture antigens and recognize danger signals. After antigen uptake, DCs migrate to regional draining lymph nodes for presentation of sequestered antigen. During their migration, DCs internalize and process antigen and up-regulate the expression of costimulatory molecules at their cell surface, a process referred to as maturation. In the lymph nodes, DCs present the processed antigen to naive T lymphocytes, resulting in the initiation, suppression (i.e., tolerance), or termination of adaptive immune responses if no longer needed (7). DCs thus normally control immunologic homeostasis, but may behave inappropriately in COPD.

We here summarize what is known of the effects of CS on DCs and present our perspective for plausible links between smoking, DCs, and the pathogenesis of COPD.

CURRENT VIEWS ON DENDRITIC CELLS

Classification of Pulmonary DCs
The first pulmonary DCs to be described were Langerhans cells (LCs), now recognized by their immunohistochemical expression of CD1a, langerin (CD207), and, by electron microscopy, the presence of Birbeck granules. Recently, three phenotypically and functionally different pulmonary DC subsets, such as those circulating in the human blood, have been described: (1) type 1 myeloid DCs (BDCA1 [CD1c]⁺), (2) type 2 myeloid DCs (BDCA3 [CD141]⁺), and (3) plasmacytoid DCs (BDCA2 [CD303]⁺, CD123⁺) (8–10) (Figure 1). Although several reports suggest that LCs in tissue derive from myeloid precursors in the blood (11, 12), it remains unclear if LCs in peripheral tissue (e.g., the lung) are simply a subset of myeloid DCs or should rather be regarded as a totally different DC subset, with separate functions and a distinct origin. Myeloid and plasmacytoid DCs perform different functions in both innate and adaptive immunity. At the same time, they have functional plasticity to induce appropriate T-cell responses depending on the type of stimuli.

View larger version (55K): [in this window] [in a new window]   Figure 1. Selected molecules expressed by dendritic cells (DCs). DCs express subset-specific molecules, pattern recognition receptors that activate DCs, maturation markers, such as costimulatory molecules required for the activation of lymphocytes, and receptors involved in the migration of DCs across endothelia in their recruitment to peripheral tissues and in their migration to draining lymph nodes. Subset-specific molecules are differentially expressed by distinct DC subsets (i.e., Langerhans cells [LC], conventional DCs [cDC], plasmacytoid DCs [pDC]). The lower left corner shows a bright field image of an isolated pulmonary DC with DC processes that give the cell its name.

Precursor DCs circulate in the blood in an immature form, and under steady-state conditions they migrate slowly to the lung. During an infection and/or tissue damage, resident DC populations are enriched by DCs migrating in response to the production of a large spectrum of inflammatory molecules acting on specific receptors and by differentiation of monocytes to DCs (16, 17) (Figure 1). Furthermore, upon inflammation, recruited and resident DCs become activated via recognition of pathogen- and damage-associated molecular patterns (Figure 1).

Draining Lymph Node Migration and Maturation
Pulmonary DC migration to the draining lymph nodes is triggered by antigen capture and characterized by the down-regulation of DC antigen capture capacity and the up-regulation of DC lymph node homing receptors, mainly CCR7 (18). Importantly, in the presence of pathogen- and damage-associated molecular patterns, DC migration is accompanied by full DC maturation, a differentiation process characterized by an increase in various cell surface and intracellular molecules expression (e.g., CD80, CD83, CD86, DC-LAMP [dendritic cell–lysosomal-associated membrane protein]) and proinflammatory cytokine secretion, all of which are necessary for efficient antigen presentation and T-cell stimulation (7). By contrast, in the steady state and in the absence of danger signals, migrating DCs to lymph nodes remain semi-, but not fully, mature (7).

Induction of Tolerance
DCs account for the different pathways to peripheral tolerance, which is critical to avoid pathologic reaction to self-antigens or harmless foreign antigens. Traditionally, semimature steady-state migrating myeloid DCs carry low doses of antigens, do not secret proinflammatory cytokines, and fail to stimulate the corresponding T cells. However, a growing body of evidence now indicates that DCs can also actively maintain peripheral T-cell tolerance by the induction and/or stimulation of regulatory T-cell (Treg) populations. For example, plasmacytoid DCs expressing high levels of the inducible costimulator (ICOS) ligand induce the proliferation of immunosuppressive Tregs (19). Therefore, DC maturation can no longer be used to distinguish tolerogenic and immunogenic properties of DCs.

Induction of T-cell and B-cell Responses in Lymph Nodes or Lymphoid Aggregates
Mature DCs drive the clonal expansion of T cells by displaying large amounts of major histocompatibility complex (MHC)–peptide complexes on their surface, expressing high levels of costimulatory molecules, and by releasing large amounts of proinflammatory cytokines. DCs control B-cell growth and differentiation not only through T-helper (Th) cells but also through direct action (20). In addition, DCs have the capacity to control Th1/Th2 balance and to evoke the recently identified proinflammatory Th17 cell response (21, 22). The resulting balance depends not only on the subset of DCs presenting the antigen but also on the antigen type and dose and the presence of polarizing cytokines and other receptor stimulants. The most critical DC-derived factor favoring Th1 differentiation has been long considered the production of IL-12. However, recent studies indicate that CD70 and Notch ligand Delta expressed on myeloid DCs are IL-12–independent Th1-inducing factors (23, 24). It remains to be clarified how DCs instruct Th2 differentiation—that is, whether Th2 differentiation is caused by a default fate in the absence of IL-12, or requires a positive Th2-instructive signal. In support of the second concept, DCs expressing OX40 ligand and Notch ligand Jagged preferentially induce Th2 responses (24, 25).

Maintenance of Immune Responses in Lung Tissue
Pulmonary DCs maintain immune responses by stimulating primed T cells and "memory" cells to become effector T cells (26, 27). Moreover, they retain the capacity to present antigen to T cells for several months (28).

Interface of DCs with COPD
Although the involvement of DCs in asthma, pulmonary infections, lung transplant rejection, and lung cancer is established, their role in COPD has been little studied (17). However, in vitro cell studies and in vivo animal and recent human studies demonstrate alterations in their number and function and support a role for DCs in the pathogenesis of COPD.

DC ALTERATIONS INDUCED BY CIGARETTE SMOKE

In Vitro Cell Studies
Studies of the suppressive effects of CS components on leukocyte function were recently extended to include effects on DCs.

Exposure of DCs to nicotine.
Low doses of nicotine may increase DC maturation and their capacity to secrete IL-12 and to induce T-cell proliferation (29), whereas higher doses are associated with low endocytic and phagocytic function, decreased IL-12 release, and a decreased capacity to induce T-cell proliferation and Th1 differentiation after stimulation (30). Human monocyte–derived DCs differentiating in a nicotinic environment produce less IL-12, produce more of the Th2 cytokine IL-10, and exhibit a reduced capacity to induce naive T-cell differentiation in the direction of effector Th1 cells (31). On the contrary, in a Th2-prone milieu, nicotine-differentiated DCs prime Th2 cell differentiation more efficiently (31).

Effects of CS Extract Exposure.
Exposure of human monocyte–derived DCs to CS extract (CSE), generated by the passage of mainstream smoke into medium, significantly impairs the capacity of DCs to induce T-cell proliferation and Th1 differentiation, whereas it increases DC-dependent Th2 differentiation (32). In addition, CSE suppresses LPS-induced DC maturation, and enhances IL-10 and prostaglandin E2 release (32). It is unlikely that these effects are mediated solely by nicotine, because CSE is a complex of a multitude of chemicals in which nicotine is present in relatively low concentration.

Exposure of DCs to lung secretions.
The sputum of patients with COPD inhibits LPS-induced maturation of murine DCs, DC-dependent T-cell proliferation, and differentiation toward the Th1 phenotype in vitro. These inhibitory effects of sputum are partly mediated via the effects of included neutrophil elastase (33).

In conclusion, in vitro cell studies suggest that CS has a dose-dependent effect on DC maturation, suppresses their T-cell stimulatory capacity, and reduces their capacity to induce Th1 polarization. These effects may be mediated through several CS components, which include nicotine, and/or through inflammatory mediators, such as neutrophil elastase, released into the lungs of smokers and patients with COPD.

In Vivo Animal Studies
In an early study, CS exposure of mice increased their numbers of pulmonary LCs and showed histologic changes consistent with an LC histiocytosis (34). More recently, the effects of CS on DCs have been studied in murine models of CS-induced emphysema.

Experimental models of emphysema in mice.
Mice exposed subacutely to low doses of CS (i.e., 2 cigarettes/d) show reduced numbers of myeloid DCs and DC expression of CD80 in lung tissue digests (35). Although these mice showed evidence of emphysema, this was not associated with marked tissue inflammation at any of the time points investigated, suggesting that this does not ideally model the emphysema described in some patients with COPD.

In contrast, higher doses of CS (i.e., 20 cigarettes/d) have been shown to increase pulmonary myeloid DC numbers and up-regulate DC expression of MHCII, CD40, and CD86 in the bronchoalveolar lavage fluid (BALF) of mice (36). These mice developed both chronic airway inflammation and emphysema, and CO levels in the blood were comparable to the CO levels measured in human smokers. It appears that high-dose CS-induced accumulation of DCs in the lungs may be mediated partly through CCR6 and its ligand monocyte inflammatory protein (MIP)3, because CS-exposed CCR6 knockout mice showed a reduced accumulation of pulmonary DCs (37).

In conclusion, in vivo evidence from murine models of CS-induced emphysema supports the hypothesis that CS exposure has modulatory effects on pulmonary DC numbers and their maturation. Whether CS in humans has a predominantly immunosuppressive or immunostimulating effect likely varies with individual genetic profile, manner of smoking, and pack-years smoked. The response within the lung may also vary by airway generation as smaller (more distal) airways will receive relatively lower doses and less of the particulate fraction of the smoke on average than larger (more proximal) bronchi.

Human Studies
There are few studies on the effects of smoking on pulmonary DCs in humans.

Methodologic issues.
There are apparently conflicting results in the sparse human literature on this topic and this may be due to application of distinct DC-specific markers, sampling of different anatomic sites (airway generations), and because of distinctions as to whether the findings are due to smoking per se (independent of the presence or absence of COPD) or the disease process itself. As an example of the first issue, langerin and CD1a are considered to be markers of an immature myeloid DC phenotype, whereas CD83 and DC-LAMP are considered markers of mature DCs (Figure 2).

View larger version (74K): [in this window] [in a new window]   Figure 2. Dendritic cells (DCs) in the small airways of subjects with chronic obstructive pulmonary disease immunostained to show expression of (left panel) langerin (CD207)-positive immature cells (brown) located mainly in or close to the airway epithelium and (right panel) CD83+ (mature) cells (red) located mainly in the subepithelial zone of the airway wall (stained with peroxidase and alkaline phosphatase anti-alkaline phosphatase techniques, respectively).

In the lungs of patients with COPD.
No significant differences have been reported in mucosal CD1a⁺ immature DCs of large airways in smokers with COPD as compared with healthy smokers (43). Recent data also suggest no significant differences in the number of CD1a⁺ DCs in the small airways of patients with COPD compared with smokers without COPD (44). By contrast, in small airways, there is a significantly increased number of langerin (CD207)-positive immature LCs in the epithelium and adventitia of patients with COPD when compared with never-smokers and smokers without COPD; moreover, the highest numbers of immature DCs are reported in patients with the most severe COPD (45).

Thus, a limited number of studies in humans have evaluated the effect of cigarette smoking on DC numbers in the lungs of healthy smokers and patients with COPD. These studies describe either no effect or an increase in the number of alveolar langerin–positive and CD1a⁺ immature DCs in response to chronic cigarette smoking. There was a similar increase in langerin-positive immature DCs (i.e., LCs) in the small airways of patients with COPD, whereas CD1a⁺ DCs showed no differences between patients with COPD and smokers without COPD (40). In contrast, in large airways, current smoking appears to decrease the number of mature DCs both in the bronchial mucosa (in patients with asthma) and in induced sputum of healthy smokers (41, 42). Unlike the reports in animals (35, 36), the effects of smoking on DC expression of costimulatory molecules have not yet been investigated in humans.

Depending on the marker (langerin, CD1a, CD1c) used to identify DCs and on their localization in the human lung (i.e., large airways, small airways, or alveoli), different and at first sight conflicting results on the number and function of DCs in COPD are obtained. Future studies should investigate whether langerin, CD1a, and CD1c are all markers of the same subtype of DC in human lung, or instead reflect the presence of three different DC subsets in human lung. Double and/or triple immunohistochemical stainings and multicolor flow cytometry with cell sorting and subsequent functional analyses should allow more detailed information on this subject to be obtained.

HYPOTHESIS LINKING DCS TO COPD PATHOGENESIS

We consider it highly likely that DCs are implicated in the pathogenesis of COPD, not only in the initiation but also in the perpetuation of its characteristic pattern of chronic airway inflammation. Our working hypothesis is illustrated in Figure 3. CS- and oxidant-induced lung tissue damage and/or microbial colonization will normally induce synthesis and release, mainly by bronchial epithelial cells, of a variety of DC-attracting signals, including chemokines, defensins, and heat shock proteins, and these will recruit circulating immature DC precursors to the lung (17, 36, 37, 45). MIP-3 (CCL20) and CCR2 ligands (monocyte chemotactic proteins [MCPs]) acting on the CCR6 and CCR2 receptors, respectively, appear to be key to the accumulation of mucosal DCs in response to CS (37, 46–48). Resident DCs may also be activated via broad-based recognition of infection by cell surface Toll-like receptors and other pattern recognition receptors (Figure 1). As shown in animal studies, the increase of DCs may be one important source of the released matrix metalloproteinases (MMPs), including MMP-9 and MMP-12, which are implicated in the development of emphysema (17, 49). Once activated, DCs are encouraged to mature and migrate to draining lymph nodes by chemoattractants, including MIP3β acting on cell surface receptors such as CCR7. Depending on the nature of the initial stimulus, DCs will cooperate with naive lymphocytes to induce one of three predominant responses: Th1, Th2, or Treg, the last associated with the development of tolerance.

View larger version (44K): [in this window] [in a new window]   Figure 3. Theoretical schema by which pulmonary dendritic cells (DCs) might be implicated in chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)–induced lung tissue damage, inflammation, and microbial colonization/invasion activate the production of DC-attracting chemokines, including CCR6 ligands (MIP3 and β-defensins) and CCR2 ligands (MCP1–4), encouraging a large number of circulating immature DC precursors to emigrate from the blood to be retained in the bronchial mucosa and lung parenchyma (1). Recruited DCs capture "foreign" antigen, originating exogenously or endogenously as altered or normally sequestered self-antigens to induce a DC response. However, CS exposure per se, as well as alveolar macrophages and CS-exposed epithelial cells, impair the normal process of DC maturation (2). Thus, non- or partially matured and/or functionally impaired pulmonary DCs reach the draining lymph nodes (LN) or lymphoid aggregates/follicles within the airway wall itself (3). CS-impaired DCs fail to induce appropriate T-cell responses but instead induce predominantly CD8+ T cell proliferation (4) that migrate away from the node to accumulate in the conducting airways and lung parenchyma (5). The recruited CD8+ T cells release perforin and granzymes, resulting in host tissue cell apoptosis/death and the release of factors that recruit more DCs, which together with macrophages release matrix metalloproteinases, including MMP12, that finally damage tissue (6). DCs may retain antigen for presentation to T cells over long periods where such chronic inflammation eventually leads to emphysema and /or the small airway changes associated with the progressive accelerated decline in lung function characteristic of COPD.

Normally, exposure to "danger" signals would recruit DCs and initiate the process of DC maturation and their migration to regional lymph nodes in a fully mature state to induce specific immunity. However, the crux of our hypothesis is that CS exposure, while recruiting increased numbers of (langerin-positive) immature DCs impairs such DC maturation (detected as reduced CD83 expression), altering and suppressing normal DC function (30–32, 35, 41, 45), either directly or indirectly through increased alveolar macrophages and macrophage nitric oxide production and/or through suppression of epithelial cytokine cell release and inhibition of costimulatory molecule expression, are critical to DC maturation (46, 52). These alterations may significantly affect the capacity of DCs to induce immune responses that normally and appropriately protect the respiratory tract from infections. Such abnormal DC responses will favor repeated microbial and viral invasion and increased frequency of exacerbations, and contribute to the altered pattern of inflammation associated with acute worsening of COPD (2).

In addition, CS-induced impairment in DC maturation may enhance CD8⁺ T-cell proliferation via increased cross-presentation of foreign and self-antigens. In support of this, FcR-mediated cross-presentation is tightly regulated during DC maturation: cross-presentation increases soon after activation by LPS and it is then inhibited in fully mature cells (53). The organization of lymphocytes into lymphoid follicles, such as those described in association with the small airways of patients with severe (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages 3 or 4) COPD, strongly suggests that T-cell proliferation takes place in the lungs of patients with COPD (3, 54). Importantly, tissue damage associated with repeated CS exposure may unmask intracellular self-proteins or alter normally nonantigenic proteins to be recognized as "nonself." Cross-presentation of self-antigens, such as elastin, endothelial antigens, or epithelial antigens by DCs to CD8⁺ T cells could lead to development of autoimmunity (55, 56). Together with the capacity of DCs to preserve antigens for presentation to T cells for several months, such chronicity of stimulus will perpetuate the inflammation even when smoking ceases (28, 57). These hypotheses, illustrated in Figure 3, require testing in animal models of emphysema and investigation in humans.

CONCLUSIONS

There appears to be an immune basis for the chronicity, amplification, and abnormal pattern of inflammation now enshrined in the definition of COPD. DCs normally play a major role in the initiation and orchestration of immune responses. There is evidence in humans to show that CS induces the recruitment of a large numbers of immature DCs into the small airways of patients with COPD. We hypothesize that chronic exposure to CS impairs the normal maturation process of DCs and subsequently alters/suppresses their normal function and interaction with naive lymphocytes, resulting in an imbalance of immunity that may increase susceptibility of patients with COPD to respiratory infections. DCs are becoming newly recognized for their role in the pathogenesis of COPD, an old disease with ever increasing global impact. Future advances in our knowledge about pulmonary DCs combined with recent advances in the pharmaceutical manipulation of DC function may help in the discovery of novel therapeutic modalities with which to prevent or treat COPD more effectively.

Acknowledgments

Note added in proof: Subsequent to the acceptance of this work, the authors have located published evidence demonstrating that increases in C-reactive protein, such as those that occur in COPD, can alter DC differentiation and function and reduce DC maturation (Zhang R, Becnel L, Li M, Chen C, Yao Q. C-reactive protein impairs human CD14⁺ monocyte-derived dendritic cell differentiation, maturation and function. Eur J Immunol 2006;36:2993–3006).

The authors thank Professor Guy Joos (Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium) for careful and critical reading of the manuscript.

FOOTNOTES

Supported by Imperial College London departmental funds.

Originally Published in Press as DOI: 10.1164/rccm.200711-1727PP on March 12, 2008

Conflict of Interest Statement: M.T. has been reimbursed by GlaxoSmithKline (GSK), AstraZeneca (AZ), and Boehringer Ingelheim for attending conferences and has received a research grant from GSK. I.K.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.G.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.K.J. has been reimbursed by GSK, AZ, and Merck, Sharpe, & Dohme (Merck) for attending conferences and has participated as a paid speaker in scientific meetings or in courses organized and financed by GSK, AZ, and Merck. P.K.J. has served as a consultant to GSK, Argenta Discovery, and Novartis; he has received research grants from GSK ($750,000), Merck ($120,000), and AZ ($540,000); he has shares in GSK.

Received in original form November 23, 2007; accepted in final form March 12, 2008

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