The Proceedings of the American Thoracic Society 2:116-120 (2005)
© 2005 The American Thoracic Society
Pulmonary Dendritic Cells in Local Immunity to Inert and Pathogenic Antigens in the Respiratory Tract
Patrick G. Holt
Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, The University of Western Australia, Perth, Western Australia, Australia
Correspondence and requests for reprints should be addressed to Professor P. G. Holt, Division of Cell Biology, Telethon Institute for Child Health Research, PO Box 855, West Perth, WA, 6872, Australia. E-mail: patrick{at}ichr.uwa.edu.au
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ABSTRACT
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Subsets of dendritic cells form a series of highly developed networks throughout the respiratory tree, and represent the only professional antigen-presenting cells present within the majority of these tissue microenvironments. Work in noninfectious model systems indicates that they function with high efficiency in immune surveillance for inhaled antigens, responding rapidly to local antigenic challenge via mobilization of resident and precursor populations with kinetics equivalent to neutrophils. Their prime function is to rapidly translocate incoming antigenic signals to the lymph nodes draining the mucosal surfaces of the respiratory tract, and as such they are ideally positioned to orchestrate primary and secondary adaptive immunity to all classes of inhaled antigens, in particular those derived from pathogens such as respiratory viruses.
Key Words: dendritic cells • pulmonary • T cells
The mucosal surfaces of the respiratory tract present a fragile interface between the immune system and the antigen-rich external environment. The array of antigens encountered at these surfaces on a daily basis is vast, and poses a major challenge in relation to maintenance of local immunologic homeostasis and hence tissue integrity. The task continually confronting the immune system is classification of incoming antigens into appropriate classes (particularly pathogenic versus nonpathogenic), and subsequently tailoring defense responses to optimally match the challenge. It has become clear that local populations of dendritic cells (DCs) play essential gatekeeper roles in this process. This article focuses on essential aspects of their functions in local immunoregulation, concentrating initially on control of responses to inert protein antigens, for which a substantial background literature exists, and then on the less well understood area of host defense against microbial pathogens, particularly viruses.
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DC NETWORKS IN RESPIRATORY TRACT TISSUES: IMMUNOMORPHOLOGIC CHARACTERISTICS
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Populations of DCs are widely distributed throughout the tissues of the conducting airways and the peripheral lung. The most notable of these comprise a contiguous network comparable to the epidermal Langerhans cell population of the skin, which is found within and beneath the conducting airway epithelium. The network is virtually identical in human (1) and murine tissues (2–4), and within the epithelium comprises 500 to 750 cells per square millimeter of epithelial surface. The cells constituting this substantial intraepithelial population exhibit the characteristic highly dendritiform morphology of mature interdigitating DCs and express high levels of surface MHC class II in the absence of coexpression of macrophage or B cell markers (5). Other markers that are expressed on these cells, and that have varying degrees of specificity for DCs, include CD1a and/or CD1c in humans and NLDC-145 in mice. Below the epithelial basement membrane, a further and larger DC population exists, which by confocal microscopy can be estimated at 2.5- to 3.5-fold larger in the steady state than their counterparts within the epithelium. These cells exhibit a more heterogenous morphology, ranging from relatively small regular shaped cells resembling monocytes, through to classical dendritiform DCs. Our recent evidence (discussed below) suggests that this latter population comprises a mixture of recently recruited precursor DCs newly arrived from the peripheral circulation, many of which are en route to the overlying epithelium, and mature antigen-laden DCs en route from the epithelium to draining lymphatics.
In addition to these airway mucosal populations (AMDCs), substantial populations of DCs exist within the nasal mucosa (6) and adjacent turbinates (7), as well as in peripheral lung tissues, including the pleura and connective tissues surrounding blood vessels (5, 8–10). Further DC populations have been identified by bronchoalveolar lavage in the alveolar spaces (11, 12), and an additional precursor DC population has been identified in the vascular compartment of the lung (13).
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DC HETEROGENEITY WITHIN RESPIRATORY TRACT TISSUES
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Earlier studies from our group (5) and others (14–16) involving immunohistochemical staining of DC populations in frozen sections of airway versus peripheral lung tissues from several species, identified considerable heterogeneity in surface marker expression within and between these two sites in the respiratory tree. Comparable findings indicating heterogeneity have come from analyses on DCs prepared from collagenase digests of whole lung (17, 18). It is additionally noteworthy that Birbeck granules, which are a frequent finding in epidermal Langerhans cells, are detectable in only a small subset of DCs in these respiratory tract tissues (9, 14, 19).
Increasing attention is being paid to the relative contribution of the myeloid versus plasmacytoid subsets to the overall DC population in the respiratory tract. Both DC types have been identified in bronchoalveolar lavage fluids (20) and in the lung parenchyma (19), as well as within the nasal mucosa (21). In contrast, the plasmacytoid DC population is not observed in resting bronchial mucosal tissues or during the late phase response of atopic individuals with asthma (22), although it is possible that they may be recruited at a subsequent stage of the inflammatory process.
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POSTNATAL DEVELOPMENT OF DC NETWORKS IN THE RESPIRATORY TRACT
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Murine studies have identified only small populations of DC-like cells within the airways and peripheral lung tissues during late fetal life (7, 10), indicating that the establishment of these cellular networks essentially occurs postnatally. In the species in which this developmental process has been studied in most detail, the rat, it is noteworthy that the kinetics of network establishment follows a relatively protracted time course, and does not resemble that in adult tissues until several weeks beyond biological weaning age (7, 23). Moreover, postnatal development involves not only the progressive build-up of numbers of resident intraepithelial DCs, but also a steady increase in basal levels of MHC II expression (7), which implies that local microenvironmental control of the function(s) of these cells may also alter with age.
Of additional note, the development of the network appears to occur most rapidly at sites of maximal environmental antigen exposure, notably the nasal turbinates and the large conducting airways, and speed of development overall is inversely related to depth within the respiratory tree (7). This finding is consistent with a major "driving" role for environmental irritant exposure, in setting the resting status of this population during the early postnatal period. The situation with respect to the ontogeny of human respiratory tract DC populations is less well understood. However, the available evidence suggests that these populations are sparse at birth, and normally expand relatively slowly during infancy, except in subjects with recurrent infections (24), suggesting that the overall developmental pattern is qualitatively similar in humans.
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POPULATION DYNAMICS OF LUNG DC POPULATIONS
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Steady State
DC populations in the bulk of peripheral tissues are renewed relatively slowly, exemplified by the Langerhans network in the epidermis in which the turnover time is in excess of 21 days. The life cycle of peripheral tissue DC populations is assumed to involve a bone marrow origin, recruitment to peripheral tissue sites as immature precursors, and migration on to draining lymph nodes (or spleen) after a period of antigen sampling in the host tissue. However, this model may not necessarily apply to all DCs, or to all DCs of individual DC subsets, given the now acknowledged importance of local microenvironmental control of DC functional phenotype(s). It is pertinent to compare the situation relevant to macrophages such as the pulmonary alveolar macrophage (PAM) population. It has long been established that in the steady state, the bulk of the PAM population is renewed from local lung-derived precursors (25, 26), and that incoming monocytic precursors from the bone marrow are only important in the accelerated population turnover necessitated by local inflammatory challenge (27). Given that macrophages and myeloid DCs share a common precursor, it can logically be questioned whether the model above is indeed applicable to DCs in tissues such as lung.
A series of experiments from our group has addressed this issue in detail. We have demonstrated in rat that resting AMDC populations can be rapidly depleted by either topical or systemic corticosteroid treatment or X-irradiation (28, 29), and that renewal of the bulk of these populations occurs via influx of bloodborne bone marrow–derived precursors (29). Recruitment of precursors in the steady state in the rat can be blocked, but only by 50 to 60%, by the CCR1/CCR5 antagonist metRANTES, indicating that more than one class of chemokines are involved in regulating this process at baseline (30). Recent evidence suggests that CCR6-dependent chemokines may also play a major role (31). The half-life of the bulk of the AMDC population is in the order of 36 hours, rivaling in turnover time that of the DC population of the intestinal wall (29). The rapid steady-state turnover of DCs at these two principal mucosal sites presumably reflects the importance of the immune surveillance role of local DCs in these antigen-rich microenvironments.
Airway Challenge with Soluble Proteins and Microbial Antigens
The high turnover rate of AMDCs in the steady state can be rapidly accelerated by challenge of airway surfaces with proinflammatory agents such as bacterial LPS (32) or heat-killed bacteria (33). The kinetics of these responses rival those of neutrophils. Of particular note, the capacity to mount these rapid responses to bacterial challenge is markedly attenuated during the preweaning period in rodents (29), suggesting either diminished local chemokine production in the airways of immature animals, or reduced precursors during this period. This may account in part for the increased susceptibility of young animals to respiratory infections.
It is also evident from studies in adults rats that chronic inflammation is associated with major persistent changes in airway epithelial DC populations. In particular, chronic exposure to dusty bedding increases numbers and levels of MHC class II expression on AMDCs (32). Part of these effects may be due to increased local production of inflammation-associated cytokines such as IFN-
, as administration of recIFN- to rats has also been shown to promote DC accumulation in the lungs (34).
In addition, exposure to inert protein antigens such as ovalbumin (OVA) can also elicit rapid recruitment of AMDCs, provided animals are preimmunized to generate antigen-specific T cell help (35, 36). It is noteworthy that this DC response, unlike that to a bacterial stimulus, is not susceptible to blocking by CCR1/CCR5 antagonist (30). Further in vitro studies revealed that lung DCs are responsive to virtually the full spectrum of C-C chemokine family members, as well as C5a and N-formyl-methionyl-leucyl-phenylalanine, which accounts for their capacity to mobilize in response to such a wide range of stimuli (30).
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IMMUNE SURVEILLANCE OF LOCAL MUCOSAL SURFACES BY RESPIRATORY TRACT DCs
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Analogous to findings in other tissues, it is now accepted that the primary function of peripheral lung DCs and AMDCs is acquisition of samples of inhaled antigen and translocation of these samples to regional lymph nodes (RLNs). We and others (36, 37) have recently formally demonstrated active transport of fluorochrome-labeled antigen applied to the tracheal luminal surface, to T cell regions in RLNs. In follow-up experiments (F. L. Jahnsen and P. G. Holt, unpublished observations) we have shown with dual-color labeling that antigens applied simultaneously to the tracheal surface and to the peritoneal cavity, which are both drained by the parathymic LNs (PTLNs) in the rat, subsequently localize within different DCs in the T cell regions of PTLNs; DCs containing both labels have not been detected. The latter observation indicates that tissue-dwelling DCs are the sole mode of antigen transportation to this site, and that transport of free antigen and subsequent uptake by resident LN DCs does not occur.
It is not clear how mucosal-dwelling DCs such as AMDCs sample antigens from the luminal surface, through an intact airway epithelium which is "sealed" via apical tight junctions between epithelial cells (5). Recent studies in the gastrointestinal tract have demonstrated that in some circumstances local DC projections can broach tight junctions and sample bacteria in the gastric lumen (38), and our ongoing investigations employing confocal microscopy have identified comparable activity within the AMDC population (F. L. Jahnsen and P. G. Holt, unpublished observations). In contrast to the uncertainties surrounding how physical contact is achieved between inhaled antigen and AMDCs, the mechanism of antigen acquisition by resident AMDCs once contact is established is well understood. It is clear that a subset of these cells defined by high side scatter characteristics and high surface expression of MHC II are highly endocytic (36). This subset appears to be at the more "mature" end of the differentiation continuum that is evident within this population, and are thus likely to have derived from weakly endocytic monocyte-like precursors that migrate via the airway submucosa into the overlying epithelium, for antigen sampling, progressively upregulating their endocytic capacity with time (36). Indirect evidence also indicates that AMDCs exhibiting this phenotype are poised as this stage of their differentiation to rapidly migrate to RLNs, as soon as they receive appropriate mobilization signal(s).
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CONTROL OF LOCAL T CELL RESPONSES IN THE RESPIRATORY TRACT BY AMDCs: LESSONS FROM ALLERGY MODELS
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A hallmark feature of immunologic homeostasis in the respiratory tract is nature of the baseline "default" response to initial encounters with newly encountered inert (soluble protein) antigens. This comprises an initial low-level Th2-mediated response followed by a form of "split tolerance" involving highly efficient suppression of Th2-mediated IgE production and Th1-mediated DTH, while still permitting ongoing low- to mid-level IgG antibody production (39, 40). A variety of evidence indicates that comparable mechanisms are operative in humans, and form the basis for resistance amongst the majority of the population to respiratory allergy.
Recent studies from our group strongly argue that the basis for this default response is the functional phenotype of the AMDC population in the resting state. We and others have shown that while DCs freshly isolated from whole lung or conducting airway tissues (18, 36, 41) are strongly endocytic, they function poorly as antigen-presenting cells (APCs) in vivo or in vitro, and are capable of delivering only weak Th2-polarizing signals to naive T cells (18). They require a maturation step driven by GM-CSF in conjunction with co-signals such as tumor necrosis factor-
or CD40L before switching to efficient APC mode. In the steady state, their default cytokine program appears based upon interleukin (IL)-10, and this switches toward IL-12 following receipt of maturation signals, which also provides a mechanism for the drift from Th2-dependent low-level IgE toward low-level Th1 reactivity (including Th1-dependent IgG subtypes). Based on experience from other tissues, it appears likely that this maturation process normally occurs only after migration of the AMDCs to RLNs, thus effectively "compartmentalizing" immune surveillance in such a way that the site of antigen exposure (i.e., the delicate mucosal surfaces of the respiratory tract) are protected from the bulk of potentially tissue-damaging T cell activation events driven by inhaled protein antigens present in the airborne environment, the vast majority of which are nonpathogenic.
However, this begs the question of what occurs when the host requires rapid mobilization of T cell–mediated defenses locally within the airway wall, such as during reexposure to a pathogen. How is this deficiency in local APC function overcome?
Recent studies in our group examining Th1-polarized and Th2-polarized recall responses to OVA have provided a plausible model for what may occur in this situation (36). Thus, aerosol challenge of primed animals with OVA (and challenge of sensitized humans with allergen [22]) elicits rapid influx of fresh DC precursors, and over the next few hours the efflux of resident allergen-bearing DCs to RLNs. However, kinetic studies have revealed the sequential operation of a complex series of immune mechanisms through which the local immune system mobilizes a "burst" of local T cell reactivity, which is then terminated in order to limit local damage to tissues. This sequence of events occurs as follows (36):
- Inhaled antigen is acquired by a highly endocytic subset of "semi-mature" AMDCs, which initially lack APC activity;
- A burst of local chemokine activity is generated which recruits in fresh immature and weakly endocytic DCs as well as T cells and granulocytes;
- Resident AMDCs are continually clustering temporarily with recirculating T-memory cells transiting the tissue; when such an encounter involves an OVA-bearing DC and an OVA-specific Th-cell, back signaling (presumably via CD40L) from the T-cell to the DC rapidly ignites the latter's differentiation/maturation program, triggering rapid shutdown of endocytosis, mobilization of OVA-peptide/MHC II complexes to the cell surface, expression of costimulators (previously lacking) such as CD86, and cell–cell interaction molecules such as ICAM-1;
- The rapidly maturing DC becomes progressively chemokinetic, seeking an exit toward the draining lymphatics; this emigration process takes several hours, during which (many) further interactions occur with incoming OVA-specific Th-memory cells; these "second tier" cognate interactions now provide full activation stimuli to the T cells involved;
- Within 12 to 24 hours, all antigen-bearing DCs have relocated to the RLNs, where they contribute to expansion of central memory, leaving in their wake in the airway mucosa a population of Th-cells bearing IL-2R, which secrete whatever repertoire of cytokines is dictated by their respective memory programs; in the allergy model, this can result in a transient wave of airways hyperresponsiveness, as an indirect result of local cytokine secretion;
- The T cell activation response then shuts down, DC recruitment ceases, and immunologic homeostasis is reestablished.
The rate-limiting step in this process is expression by AMDCs of costimulators such as CD86, triggered directly via initial cognate interaction(s) with Th-memory cells before initiation of emigration (36). It is important to note that this sequence of cell-mediated events is common to both Th1 and Th2 recall responses, and this is likely to also occur in the context of airway challenge with infectious agents. However, as discussed below, relatively little is as yet known of the precise details of this process during infectious episodes.
It is pertinent to note here that experimentally induced hyperexpression of DC-maturing cytokines such as GM-CSF in respiratory tract tissues can markedly promote immune responses to inhaled protein antigens (42), and environmental stimuli capable of triggering similar local cytokine responses may thus be important factors in driving the pathogenesis of airway inflammatory diseases. One such example may be atopic asthma, in which hyperproduction of GM-CSF within the airway epithelium is a hallmark feature (43).
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HOST DEFENSE AGAINST RESPIRATORY VIRAL INFECTIONS: PARTICIPATION OF LOCAL DC POPULATIONS
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Research in a variety of nonrespiratory models has established the central role of DCs in antiviral defense. Innate resistance to viral infections depends principally upon type I interferons (IFN-/ß) which inhibit viral replication and upregulate MHC class I expression on viral-infected cells, and additionally activate cytotoxic natural killer cells, which kill viral-infected targets. An important source of IFN-/ß are the "natural interferon"–producing cells, which migrate into sites of viral challenge (44). Recent evidence strongly suggests that these latter cells are identical to the precursors of plasmacytoid DCs (45, 46). This DC subset plays a key role in initiating adaptive immune responses to viral infections (47), including respiratory pathogens such as influenza (48); however, nonplasmacytoid populations also appear to be involved (49, 50).
In vivo studies on the role of airway mucosal and peripheral lung DC populations in initiation of primary and secondary immunity to respiratory virus are at a relatively early stage of development. However, certain key observations suggest that further application and extension of the general principles developed in the studies above from nonviral models is likely to yield highly relevant information in this regard.
In particular, it is clear that as with other potentially inflammatory agents, airway mucosal challenge with live virus triggers large-scale recruitment of fresh DCs into the airway wall (35, 51) and subsequent translocation of many of these cells into RLNs (52). There is additionally indirect evidence that these migrating DCs prime CTL responses in draining lymph nodes (53), and also stimulate extra lymphoid production of IgA (54). Initiation of the recruitment process coincides with the first appearance of viral nucleoprotein within the infected airway epithelium (51). However, in contrast to the situation observed with host responses to bacterial stimuli (33) or soluble protein recall antigens (35, 36), the DC response to virus has a much more protracted time course even when viral clearance is rapid, and the AMDC population remains markedly expanded for more than 10 days after viral clearance. This suggests that airway viral infection potentially disturbs immunologic homeostasis within the airway wall not only during primary infection but during the recovery phase. In this context it has been long recognized that viral infections can function as exacerbating agents for asthma and in some circumstances can trigger atopic asthma de novo, including via promotion of sensitization to allergens to which the infected host was previously tolerant. It is noteworthy that this phenomenon can now be modeled in the mouse by coadministration of soluble protein antigen with live influenza virus (55), and more detailed investigations on the role of AMDCs in this process are likely to be productive.
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CONTROL OF VIRAL INFECTION BY RESPIRATORY TRACT DCs: UNRESOLVED ISSUES
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As noted above, this area of research is still in its infancy, and a range of key issues remain to be elucidated. Prominent among these are:- The role of DC subjects in primary and secondary antiviral immunity in the respiratory tract; while plasmacytoid DCs clearly play a major role, myeloid DCs are also likely to make important contributions to resistance; of particular interest is the potential "tolerogenic" role of plasmacytoid DCs in the lung, which have the potential to perform an additional function in attenuating inflammation (56), and may thus contribute to the reestablishment of local immunologic homeostasis after clearance of pathogens.
- Defense in the upper versus lower respiratory tract may well operate via subtly different mechanisms, given current understanding of the fundamental differences between resident DC populations at these related but microenvironmentally disparate sites; as outlined in detail in Reference 36, these differences limit the use of experimental infection models in which the role of DCs in host defense is assessed solely using cells prepared from "whole lung" digests, in contrast to those that employ DCs prepared from specific tissue microenvironments within the upper and lower respiratory tract.
- DC-mediated anti-viral defense in infant animals will predictably operate very differently than that in mature animals, given the major developmental constraints upon AMDC function during the early postnatal period. Given the status of this DC population in neonates, it remains debatable whether viral-specific T cell memory which is primed centrally in very early life can be efficiently reactivated in airway tissues during this life phase.
- The role of mucosal tolerance phenomenon in antiviral immunity has not been investigated. Given that this represents the default response in the airway mucosa, covert tolerance mechanisms triggered by subclinical airway infections may be significant in disease pathogenesis triggered by subsequent, more severe infections.
- Viral infection–mediated allergic sensitization to bystander allergens occurring through virus-induced changes in local DC populations warrants more detailed investigation.
- The role of airway mucosal CD4+ CD25+ Treg populations in modulation of antiviral T cell immunity warrants detailed study. Recent data from several sources indicate that inflammatory phenomena in general within lung mucosal microenvironments are subject to control at various levels by these cells, and they may hence play a central role in protection against viral pneumonitis. Of particular relevance to this discussion are recent findings implicating Tregs in control of the functional phenotype of DCs (56), and parallel findings on the potential for microbial pathogens to subvert host defense mechanisms via interference with Treg function (57).
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FOOTNOTES
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Conflict of Interest Statement: P.G.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form February 21, 2005; accepted in final form April 11, 2005)
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