Respiratory Tract Dendritic Cells Research Articles

Regulation of human paramyxovirus pathogenesis by pulmonary dendritic cells (158.4)

Abstract Human metapneumovirus (hMPV), is an important paramyxovirus that is associated with clinical syndromes ranging from mild illnesses, such as common cold, to more devastating conditions, such as bronchiolitis and pneumonia. hMPV has worldwide distribution and high incidence in children, elderly and immunocopromised patients. Understanding the immune mechanisms that regulate hMPV pathogenesis is important clinically for the development of new treatment strategies or novel vaccines for hMPV infection. Respiratory tract dendritic cells (DC) play a fundamental role in the immune system by bridging both innate and adaptive immunity. Therefore, we examined the role of plasmacytoid DC (pDC) in hMPV pathogenesis in an experimental mouse model of infection. Depletion of pDC resulted in an increased viral replication in the lungs from 4.3±1.3×104 to 1.7±6.1×105. However, no change in IFN-α/β production was observed. In addition, pDC-depleted mice demonstrated an exacerbated mucus production and pulmonary inflammation (>60%). Interestingly, the balance of lung DC was altered by the depletion of pDC as the recruitment of classical DC (cDC) into the lungs of infected mice was significantly incremented from 9.9±1.2×105 to 1.7±1.6×106. Finally, the production of CCL20, a DC-attracting chemokine, was also increased after depletion of pDC (>60%). In conclusion, these novel findings demonstrate that pDC play a protective role during hMPV infection by modulation of local immune responses.

Opportunities and challenges of the pulmonary route for vaccination

Introduction: The respiratory tract is an attractive target for the delivery of vaccine antigens. Potential advantages of drug delivery by means of the pulmonary route include accessibility, non-invasiveness, ease of administration, and the possibility to reach an elaborate mucosal network of antigen-presenting cells.Areas covered: This review discusses current pulmonary vaccination strategies and their advantages and disadvantages.Expert opinion: To improve efficiency of vaccination and develop new strategies, a well-founded knowledge about composition and characterization of antigen-presenting cell populations throughout the respiratory tract is essential. In particular, respiratory tract dendritic cells, as key antigen-presenting cells in the lung, constitute an ideal target for vaccine delivery. Furthermore, particle size is a key factor when designing new inhalable vaccines, as size determines not only deposition in different respiratory tract compartments, but also how an antigen and its carrier will interact with lung tissue components and immune cells. An increased knowledge of different respiratory tract antigen-presenting cell populations and their interactions with other components of the immune system will enable new targeting strategies to improve the efficacy of pulmonary vaccination.

Counter regulation of the high affinity IgE receptor, FcεRI, on human airway dendritic cells by IL‐4 and IL‐10

Immunoglobulin E is a signalling molecule within the environment of the respiratory tract, the high affinity receptor for which, FcepsilonRI, is expressed by dendritic cells (DC). Little is known, however, of the expression and function of FcepsilonRI on DC in the human respiratory tract. CD1c(+) DC were purified from surgically resected nasal turbinates of 11 atopic and 12 nonatopic patients with chronic rhinosinusitis. Expression of FcepsilonRI was determined by flow cytometry. Cytokine production by DC was determined by cytometric bead array. Expression of FcepsilonRI was significantly elevated on respiratory tract dendritic cells (RTDC) from atopic as compared to nonatopic patients. Activation of RTDC through FcepsilonRI induced production of the pro-inflammatory cytokines IL-6 and TNF-alpha, and the anti-inflammatory cytokine IL-10. The production of IL-6 and TNF-alpha was elevated in atopic compared to nonatopic patients studied. Conversely IL-10 production was elevated in nonatopic patients. Concomitant activation of FcepsilonRI and stimulation of RTDC with IL-4 inhibited production of IL-10 by RTDC. Neutralization experiments with anti-IL-10 Ab enhanced whereas addition of exogenous IL-10 to RTDC inhibited FcepsilonRI-mediated inflammatory cytokine production. The function of FcepsilonRI on RTDC from patients with rhinosinusitis is susceptible to counter regulation by IL-4 and IL-10.

Cigarette Smoke Exposure Impairs Dendritic Cell Maturation and T Cell Proliferation in Thoracic Lymph Nodes of Mice

Robbins CS, Franco F, Mouded M, Cernadas M, Shapiro SD. J Immunol. 2008;180(10):6623–6628 PURPOSE OF THE STUDY. Airborne antigens are processed and presented by respiratory tract dendritic cells (DCs). The purpose of this study was to determine the consequences of cigarette-smoke exposure on DC function in mice. METHODS. Mice were exposed to cigarette smoke 5 days per week for 1 month. There was also a control group of mice unexposed to smoke. Mice then underwent intratracheal injection of ovalbumin-fluorescein isothiocyanate (FITC) or ovalbumin and were killed at varying time points thereafter depending on the aspect of DC function being studied (migration, maturation, or T-cell activation). Lung cells were isolated, and the numbers of DCs were determined in exposed and unexposed mice by flow cytometry. Migration of lung DCs to thoracic lymph nodes (TLNs) was assessed by measuring CD11c+FITC+ cells. Maturation of TLN DCs after ovalbumin exposure was then determining by assessing expression of cell-surface costimulatory molecules (CD80, CD86, MHCII, CD40). T-cell proliferation was assessed by measuring T-cell–derived cytokine production by TLN cells in vitro. The staining profile was assessed to measure T-cell proliferation in vivo. RESULTS. The number of lung DCs was decreased among mice exposed to cigarette smoke. Exposed mice did not exhibit decreased migration of lung DCs to TLNs, as evidenced by similar numbers of TLN CD11c+FITC+ cells as in unexposed mice. Although no differences were observed in migration, smoking suppressed DC maturation in the lymph nodes as demonstrated by decreased cell-surface expression of MHC class II and the costimulatory molecules CD80 and CD86. T-cell proliferation was impaired in smoke-exposed mice, evidenced by reduced interleukin 2 production from CD4 T cells as compared with controls. T-cell proliferation was also decreased in vivo: smoke-exposed mice had a lower percentage of T cells undergoing ≥6 cycles or cell division compared with controls. CONCLUSIONS. These findings suggest that cigarette smoke is associated with defects in DC maturation and suppressed thoracic lymph node CD4+ T-cell proliferation in mice. REVIEWER COMMENTS. This study suggests that cigarette-smoke exposure in mice leads to impaired DC maturation and thereby diminished T-cell clonal expansion in the TLNs. The findings imply that, although the T-cell effector program remains intact, fewer cells might be available to perform those duties. The authors asserted that the observed effects on DC function might serve as a potential mechanism for cigarette smoke causing impaired tumor surveillance. In addition, it is suggested that impaired CD4+ T-cell function might predispose patients with obstructive lung disease to infections and exacerbations. Additional studies will help to elucidate the specific mechanisms by which cigarette-smoke exposure exerts its harmful immunologic effects.

Interaction of Respiratory Dendritic cells with Influenza Virus Infection in vitro (43.44)

Abstract Influenza A virus is a major cause of infection of the respiratory tract worldwide. Approximately 10–20% of U.S. population is estimated to be infected by this virus each year. Respiratory tract dendritic cells (RDC) are believed to play a major role as antigen presenting cells in initiating adaptive immune response to influenza virus infection. We have examined the effect of influenza virus infection of purified RDC in vitro at different MOI (Multiplicity of Infection) on virus protein expression, co-stimulatory molecules expression, and cytokines production. We found that there is not only an MOI dependent increase in the percentage of infected RDC, but also the infection of RDC at high MOI results in higher level and accelerated viral protein synthesis at early time post infection. Production of tested cytokines and chemokines by RDC increases with increasing of MOI except for IL-12 p40. Furthermore, we found that at high MOI total RDCs can be divided to several populations based on CD40 and influenza nucleoprotein (NP) expression: CD40high NPlow, CD40low NPhigh, and CD40negNPnegDCs. In conclusion, our results suggest that there is a diverse response of RDC to influenza virus at different MOI as reflected by their susceptibility to infection and cytokine production. These results may provide insight into how RDC modulate host response in the lung to influenza virus infection. (Support: USPHS grant, NIH AI-15608, HL-33391,HL-71875)

Mouse respiratory tract dendritic cell subsets and the immunological fate of inhaled antigens

It is widely accepted that tissue dendritic cells (DC) function as immune sentinels by alerting T cells to foreign antigen after delivering and presenting it in the draining lymph nodes. Over the last two decades, studies in animal models, particularly rodents, have demonstrated that respiratory tract DC are crucial for the adaptive immune response to inhaled antigen. Indeed, the fate of inhaled antigen is inextricably linked to the function of respiratory tract DC. In this review, we will discuss the characteristics of respiratory tract DC from mice and recent data that may help to explain their role in the fate of inhaled antigen.

Differential Expression of Cell Surface Markers by Ovine Respiratory Tract Dendritic Cells

Dendritic cells (DCs) are key antigen-presenting cells central to the induction of primary immune responses. Despite the prevalence of respiratory disease in sheep and the increasing use of the ovine lung as a model for human disease, ovine respiratory tract DCs (RTDCs) have not yet been characterized. Using single and double immunocytochemical staining, expression of a number of potential DC markers (MHC class II, CD1b, SIRPalpha, and CD205) by ovine RTDC populations has been determined. MHC class II staining revealed widespread populations of DCs either adjacent to respiratory airway epithelium or within the lung parenchyma. CD1b was expressed by a small subpopulation of both airway and parenchymal RTDCs. Expression of SIRPalpha was limited to a small subpopulation of airway RTDCs but was absent from the lung parenchyma. CD205 was widely expressed by airway RTDCs but expressed only by a small subpopulation of parenchymal RTDCs. In addition, the majority (87%) of parenchymal CD205+ cells exhibited a non-DC-like morphology and did not express MHC class II, suggesting that these single CD205+ cells were not DCs. Phenotypic differences between airway and parenchymal RTDCs may be related to functional differences between the two populations.

Mechanisms for inducing nasal mucosal tolerance in experimental autoimmune uveoretinitis

Delivering soluble (auto) antigenic peptides via the naso-respiratory route induces tolerance to that peptide and suppression of experimental models of autoimmune disease. In the normal lung, respiratory tract dendritic cells (RTDCs) efficiently endocytose soluble antigens, migrate to regional lymph nodes and present peptide to T cells that subsequently become tolerant. This article describes protocols for inducing tolerance via the naso-respiratory tract in experimental autoimmune uveoretinitis (EAU); for the isolation of RTDCs to facilitate definition of, and conditions for, maturation and activation of cells; and to test RTDC ability to induce tolerance in murine EAU when adoptively transferred.

Functional plasticity of human respiratory tract dendritic cells: GM-CSF enhances T H2 development

Dendritic cells within the human respiratory mucosa (RTDCs) are proposed to initiate immune responses to foreign antigens. Their capacity to polarize T-cell responses, however, has not been investigated. To compare RTDCs with peripheral blood dendritic cells (PBDCs) with regard to phenotype, cytokine production, capacity to polarize T-cell responses, and effects of exposure to the pleiotropic cytokine, GM-CSF. CD1a(+) RTDCs and CD1c(+) PBDCs were purified from nasal turbinates of patients with nonatopic rhinitis and peripheral blood of healthy individuals, respectively. In some experiments, matched CD1c(+) RTDCs and PBDCs from patients with rhinitis were compared. The phenotype of DC was examined by flow cytometry and cytokine production by cytometric bead array. DCs were cocultured with allogeneic naive CD4(+) T cells, and cytokine production was determined by immunophenotyping, cytometric bead array, and ELISA. Both RTDCs and PBDCs exhibited an immature phenotype, but RTDCs expressed lower levels of MHC class II antigen. Cross-linking of CD40 on PBDCs, but not RTDCs, induced production of IL-12p70. In mixed lymphocyte cultures, RTDCs induced a T(H)1/T(H)2 profile, whereas PBDCs induced a T(H)1 profile. Exposure of RTDCs to GM-CSF induced a T(H)2 pattern of response in the mixed lymphocyte cultures. In contrast, exposure of PBDCs to GM-CSF promoted a T(H)1 response. This report emphasizes the importance of studying tissue-derived primary DCs, demonstrates functional plasticity of RTDCs, and implicates GM-CSF in amplifying the potential of RTDCs to initiate T(H)2 responses in the airways.

No defect in T-cell priming, secondary response, or tolerance induction in response to inhaled antigens in Fms-like tyrosine kinase 3 ligand–deficient mice

Respiratory tract dendritic cells (DCs) are crucial for the regulation of immune responses to inhaled antigens. However, the precise function of the multiple DC subsets present in the lungs and the lung-draining lymph nodes is unknown. Fms-like tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that drives the development of multiple subsets of DCs in the lymphoid organs. We sought to study the contribution of DC subsets in the regulation of the balance between tolerance and immunity against respiratory antigens by using FLT3L knockout mice. Phenotypic analysis of DC subsets in the airways and lungs of FLT3L knockout mice was performed. By using various experimental models, the role of FLT3L-dependent DCs in the priming of naive T cells, the presentation of inhaled antigen to previously primed T H 2 cells, and intranasal tolerance induction was addressed. FLT3L knockout mice display a 90% reduction in lung parenchyma DCs but a normal number of airway DCs and blood monocytes. FLT3L knockout mice had a normal induction of eosinophilic inflammation in response to intranasal administration of allergen. FLT3L-dependent DCs were not required for the presentation of inhaled antigen to previously primed T H 2 cells, and normal induction of T-cell tolerance in response to inhaled antigen was observed in FLT3L knockout mice. Airway DC development is independent of FLT3L. FLT3L-dependent DCs are not required for the development and maintenance of airway inflammation or for the induction of intranasal tolerance. Our results point to airway DCs as the major regulators of the balance between tolerance and immunity to inhaled antigens.

Murine respiratory tract dendritic cells: isolation, phenotyping and functional studies

Respiratory tract dendritic cells (RTDC) form a contiguous subepithelial network within the nasorespiratory tract bridging innate and acquired immunity and have been implicated in nasal mucosal tolerance induction. Discrepancies exist between isolation techniques with respect to phenotype and function of RTDC. Therefore, the aim of this study was to modify previous methods to provide a consistent isolation method whilst maintaining good cell viability and enriched cell numbers so as to facilitate further phenotype and functional studies of murine RTDC. RTDCs isolated by enzyme digestion, Percoll density gradient centrifugation and overnight GM-CSF culture followed by MACS separation retain an archetypical immature dendritic cell phenotype, characterised by MHCII low CD40 neg CD86 neg CD80 neg CD11c low cell surface expression. Splenic-derived DC (SDC) isolated conformed to a day 1 in vitro phenotype; MHCII low CD40 neg CD86 low CD80 neg CD11c low but can further mature phenotypically in vitro. Both RTDC and SDC processed and presented antigen efficiently to T cells in vitro. Using such modified isolation procedures for RTDCs, we have developed a consistent method of RTDC enrichment, which maintains the immature phenotype and functional antigen presenting capability.

Human respiratory tract dendritic cells are susceptible to modulation by GM-CSF: Induction of a Th2 profile in naïve CD4+ T cells

Rationale Dendritic cells within the respiratory mucosa initiate immune responses to foreign and environmental antigens which are continually inhaled into the respiratory tract. We hypothesized that GM-CSF, a pleiotropic cytokine released by respiratory cells in response to allergen, could act on respiratory tract dendritic cells (RTDC) to promote differentiation of Th2 cells. Methods CD1a+ myeloid DC were purified using magnetic bead technology from nasal turbinates of non-atopic patients with rhinitis. RTDC were immunophenotyped and inflammatory cytokine production in response to LPS and CD40L determined by cytometric bead array (CBA). RTDC were cultured with allogeneic, naïve CD4+ T cells from non-atopic, healthy individuals in the mixed lymphocyte reaction and Th1, Th2 and IL-10 production determined by CBA. T cells were harvested and restimulated with mAb to CD3 and CD28. Results RTDC, which expressed an immature phenotype, responded to GM-CSF by upregulation of the maturation marker, CD83, and the co-stimulatory receptor, CD86. Exposure of RTDC to CD40L or LPS significantly increased IL-6 (p<0.05) and IL-8 (p<0.01) production but IL-12p70 production was only detectable at very low levels. In mixed lymphocyte cultures, prior exposure of RTDC to GM-CSF skewed the response of CD4+ T cells from a Th0 to a Th2 profile. Following secondary stimulation, amplification of the Th2 response was observed. CD86 was shown by inhibition experiments to be essential for Th2 cytokine production. Conclusion These results directly implicate GM-CSF in amplifying the potential of RTDC to initiate allergic inflammation in the respiratory tract

The role of dendritic cells in asthma.

The central importance of respiratory tract dendritic cells in the regulation of adaptive immune responses to inhaled antigens is now well established. Dendritic cells are not merely a conduit for the transfer of antigen to regional lymph nodes, but rather function as a sophisticated information transfer system linking the airway micro-environment to the adaptive immune system. Evidence from both animal models and clinical studies points to a critical role for dendritic cells in both allergic sensitization and the pathogenesis of chronic airway inflammation. This article reviews recent information on the distribution and function of dendritic cells in healthy individuals, the responsiveness of these cells to external stimuli, and the factors regulating their activation and turnover within the lung. Animal models of allergic airway inflammation continue to shed new light on the role of lung dendritic cells in T helper 1/T helper 2 switching, and the ability of these cells to direct regulatory T-cell development and immune tolerance. Recent studies have further characterized circulating dendritic cell populations, highlighting important functional differences between dendritic cells from atopic and nonatopic individuals, and have delineated the involvement of these cells in the late phase response to inhaled allergen. Because of the immunoregulatory properties of dendritic cells, the future is likely to see a concerted effort to further define the role that these cells play in allergic sensitization, as a basis for the development of new treatments for asthma and other atopic disorders.

Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma.

The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.

Characterization of dendritic cell populations in the respiratory tract.

Research in a variety of experimental animal species and in humans has identified dendritic cells (DCs) as the principal resident antigen presenting cells in respiratory tract tissues. The two major populations of respiratory tract DC (RTDC) comprise those found in the parenchymal tissues of the peripheral lung and in the epithelium of the conducting airways, in which they are distributed as a contiguous network comparable to the langerhans cells (LC) of the epidermis. Under steady state conditions, the airway DC population turns over every 36-48 h, whereas those in the lung parenchyma display a half-life of approximately 7 days. However, under conditions of local stress (e.g., inflammatory challenge), the turnover of these RTDC populations further accelerates, reflecting their important role in local antigen surveillance. In the resting state, they are specialized for the efficient endocytosis and processing of internalized antigens, but lack the capacity to efficiently present antigen to T-cells until they receive appropriate cytokine signals (especially GM-CSF); responsiveness to the latter is inhibited by nitric oxide, in particular from adjacent lung tissue macrophages. Our most recent findings indicate that the "default" function of resting RTDC involves selective priming for Th2 responses, and induction of optimal Th1 responses requires exposure to GM-CSF together with TNFalpha or CD40L.

Regulation of T helper cell differentiation by respiratory tract dendritic cells.

Studies on dendritic cells (DC) of the respiratory and gastric mucosae have identified an extensive network of cells that represent the predominant antigen-presenting cell type at these sites. Under steady-state conditions, respiratory tract DC (RTDC) are specialized for antigen uptake and spontaneously migrate to local lymph nodes, although in vivo transfer studies have shown that the T-cell priming activity of these cells is restricted to low-level, Th2-skewed responses. Following exposure to inflammatory stimuli, the migration of RTDC to lymph nodes is accelerated and is associated with a rapid and dramatic increase in the ability of these cells to induce both Th1- and Th2-dependent immunity. Under normal circumstances, however, responsiveness of epithelial RTDC to maturation stimuli is regulated by locally produced micro-environmental factors, including pro-inflammatory cytokines, reactive oxygen species and prostanoids. These studies have led to a greater understanding of airway DC function and their role in T helper cell differentiation and provide the basis for future studies to determine the role of the cells in the aetiology and pathogenesis of respiratory immunoinflammatory disorders.

Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity.

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the "default" T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2-3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-gamma by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing- associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor alpha or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.

Population dynamics and functions of respiratory tract dendritic cells in the rat.

The epithelial surfaces of the respiratory tract are continuously exposed to environmental antigens, and the maintenance of immunological homeostasis in this vital organ system requires efficient local mechanism for antigen surveillance, both in the steady state and during episodes of inflammatory stimulation.

Development of the airway intraepithelial dendritic cell network in the rat from class II major histocompatibility (Ia)-negative precursors: differential regulation of Ia expression at different levels of the respiratory tract.

The relative inefficiency of respiratory mucosal immune function during infancy is generally attributed to the immaturity of the neonatal T cell system. However, immune competence in the adult lung has recently been shown to be closely linked to the functional capacity of local networks of intraepithelial dendritic cells (DC). This study examines the density and distribution of these DC throughout the neonatal respiratory tract in rats, focusing particularly on microenvironmental regulation of their class II major histocompatibility complex (MHC) (Ia) expression. In animals housed under dust-controlled conditions, airway epithelial and alveolar Ia+ DC detectable by immunostaining with the monoclonal antibody (mAb) Ox6 are usually not seen until day 2-3 after birth, and adult-equivalent staining patterns are not observed until after weaning. In contrast, the mAb Ox62 detects large numbers of DC in fetal, infant, and adult rat airway epithelium. Costaining of these Ox62+ DC with Ox6 is rare in the neonate and increases progressively throughout infancy, and by weaning Ia+ DC comprised, on average, 65% of the overall intraepithelial DC population. In infant rats, Ia+ DC are observed first at the base of the nasal turbinates, sites of maximum exposure to inhaled particulates, suggesting that their maturation is driven in part by inflammatory stimuli. Consistent with this suggestion, densitometric analysis of Ia staining intensity of individual DC demonstrates that by 2-3 d after birth, Ia expression by nasal epithelial DC was comparable with that of Iahigh epidermal Langerhans cells in adjacent facial skin, at a time when expression by tracheal epithelial DC was 7-10-fold lower. Additionally, the rate of postnatal appearance of Iahigh DC in the airway epithelium was increased by administration of interferon gamma, and decreased by exposure of infant rats to aerosolized steroid. These findings collectively suggest that Ia expression by neonatal respiratory tract DC is locally controlled and can be upregulated by mediators that are produced within the lung and airway epithelium in response to inhalation of proinflammatory stimuli. It was also noted that Ialow neonatal airway DC expressed adult equivalent levels of class I MHC, which suggests differences in capacity to prime for CD8(+)-dependent versus CD4(+)-dependent immunity to inhaled pathogens, during the early postnatal period.

Dendritic Cells in the Respiratory Tract

Studies from several laboratories on lung tissue samples from human and experimental animals have identified Ia+ cells with characteristic pleiomorphic (dendritic) morphology in the epithelium and underlying connective tissue, in both the conducting airways and in the distal lung. These dendritic cells (DC) are particularly prominent within the airway epithelium, forming a contiguous network equivalent to the Langerhans cells network of the epidermis. They may be readily concentrated from enzymatically disrupted respiratory tract tissue samples on the basis of their physical properties (notably non-adherence, lack of Fc-receptors and ultra-low density on percoll), and function as highly effective antigen presenting cells in vitro. Evidence is also accumulating that respiratory tract DC populations respond dynamically to local tissue inflammation, and as such may play a prominent role in immunoinflammatory disease processes in the airways and the distal lung.