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The role of dendritic cells in asthma

2012; Elsevier BV; Volume: 129; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2012.02.028

1097-6825

Michelle A. Gill,

Immunotherapy and Immune Responses

Dendritic cells (DCs) are known to play a central role in sensing the presence of foreign antigens and infectious agents and in initiating appropriate immune responses. More recently, an additional role has been discovered for DCs in determining whether the response to potential environmental allergens will be one of tolerance or whether a vigorous response along allergic pathways will be initiated. This review discusses ways in which DCs participate specifically in initiating allergic responses, particularly those associated with allergic asthma, and how interventions focused on DCs might lead to new therapeutic approaches to asthma. Dendritic cells (DCs) are known to play a central role in sensing the presence of foreign antigens and infectious agents and in initiating appropriate immune responses. More recently, an additional role has been discovered for DCs in determining whether the response to potential environmental allergens will be one of tolerance or whether a vigorous response along allergic pathways will be initiated. This review discusses ways in which DCs participate specifically in initiating allergic responses, particularly those associated with allergic asthma, and how interventions focused on DCs might lead to new therapeutic approaches to asthma. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: April 2012. Credit may be obtained for these courses until March 31, 2014.Copyright Statement: Copyright © 2012-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Michelle Ann Gill, MD, PhDActivity Objectives1.To understand the role of dendritic cells (DCs) in the mucosal surfaces of the lung and during allergic inflammation, serving as innate sensors of foreign antigens/pathogens, and to determine whether the response to an inhaled antigen will entail the induction of tolerance or allergic inflammation.2.To present the complexities of molecular targets and chemokine interactions responsible for allergen-mediated chemotaxis of DCs to the airway and of the tuning of the magnitude of the DC response amenable to therapeutic interventions that can reduce or abolish the asthmatic allergic lung inflammation.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: M. A. Gill declares that she has no relevant conflicts of interest. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: April 2012. Credit may be obtained for these courses until March 31, 2014. Copyright Statement: Copyright © 2012-2014. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Michelle Ann Gill, MD, PhD Activity Objectives1.To understand the role of dendritic cells (DCs) in the mucosal surfaces of the lung and during allergic inflammation, serving as innate sensors of foreign antigens/pathogens, and to determine whether the response to an inhaled antigen will entail the induction of tolerance or allergic inflammation.2.To present the complexities of molecular targets and chemokine interactions responsible for allergen-mediated chemotaxis of DCs to the airway and of the tuning of the magnitude of the DC response amenable to therapeutic interventions that can reduce or abolish the asthmatic allergic lung inflammation. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. A. Gill declares that she has no relevant conflicts of interest. Dendritic cells (DCs) play critical roles in initiating and directing immune responses, serving as sentinels at the mucosal surfaces, where they constantly sample the antigens at the interface between the external and internal environment. DCs are unique in their capacity to induce primary lymphocyte responses, representing the principal cells involved in directing TH1 responses to infectious agents. DCs also play primary roles in determining the nature of T-lymphocyte differentiation in the face of allergen exposure.1Bates E.E. Dieu M.C. Ravel O. Zurawski S.M. Patel S. Bridon J.M. et al.CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily.Mol Immunol. 1998; 35: 513-524Crossref PubMed Scopus (18) Google Scholar Instructive cytokines, including IL-4, IL-12, IL-10, IL-6, and TGF-β, are known to participate in T-lymphocyte differentiation. Most of these cytokines, with the exception of IL-4, are produced by DCs themselves and are reviewed elsewhere.2Lambrecht B.N. Hammad H. The role of dendritic and epithelial cells as master regulators of allergic airway inflammation.Lancet. 2010; 376: 835-843Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 3Banchereau J. Briere F. Caux C. Davoust J. Lebecque S. Liu Y.-J. et al.Immunobiology of dendritic cells.Annu Rev Immunol. 2000; 18: 767-811Crossref PubMed Scopus (4267) Google Scholar Through mechanisms that are not yet clearly understood in the lung in vivo, DCs can drive the differentiation of uncommitted TH cells into TH2 cells, which are key mediators of allergic airway inflammation. DCs are therefore of primary importance in determining the type of TH response that is elicited on aeroallergen inhalation, and in light of this strategic role, they are poised to both direct immune responses to allergen and affect the development and perpetuation of allergic inflammation associated with asthma. The purpose of this review is to acquaint the clinician with the role of DCs in initiating and sustaining allergic inflammation associated with asthma and to point out how this knowledge could lead to new therapeutic approaches. In general, discussions begin with studies in mice and extend to available data in human subjects. Evidence supporting the participation of DCs in asthma pathogenesis is derived mainly from animal models. The role of DCs in promoting allergic inflammation and the clinical features of asthma has been primarily established in mice using an ovalbumin (OVA) sensitization model.4Wills-Karp M. Murine models of asthma in understanding immune dysregulation in human asthma.Immunopharmacology. 2000; 48: 263-268Crossref PubMed Scopus (51) Google Scholar After sensitization, which is usually induced by intraperitoneal injection of OVA in a TH2-inducing adjuvant such as alum, repeated aerosol challenges result in lung eosinophilic infiltrates and enhanced secretion of mucus by airway epithelial cells. These changes are accompanied by airway obstruction and airway hyperresponsiveness after methacholine challenge, both of which are key features of asthma. Data from animal models are robust; summary of these data into 3 key observations clearly establishes a role for DCs in the development of experimental allergic asthma.5Lambrecht B.N. Hammad H. Taking our breath away: dendritic cells in the pathogenesis of asthma.Nat Rev Immunol. 2003; 3: 994-1003Crossref PubMed Google Scholar First, significant increases in the numbers of airway DCs after exposure to allergen have been observed in both murine and rat models of asthma.6Hammad H. Chieppa M. Perros F. Willart M.A. Germain R.N. Lambrecht B.N. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells.Nat Med. 2009; 15: 410-416Crossref PubMed Scopus (374) Google Scholar, 7van Rijt L.S. Prins J.B. Leenen P.J. Thielemans K. de Vries V.C. Hoogsteden H.C. et al.Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31(hi)Ly-6C(neg) bone marrow precursors in a mouse model of asthma.Blood. 2002; 100: 3663-3671Crossref PubMed Scopus (100) Google Scholar, 8Lambrecht B.N. Carro-Muino I. Vermaelen K. Pauwels R.A. Allergen-induced changes in bone-marrow progenitor and airway dendritic cells in sensitized rats.Am J Respir Cell Mol Biol. 1999; 20: 1165-1174Crossref PubMed Google Scholar Potential mechanisms for this allergen-mediated recruitment of DCs include activation of Toll-like receptor (TLR) 4 and synthesis of β-D-glucan and matrix metalloproteinase 9 (MMP-9; see DC recruitment section). Second, it has been demonstrated that placement of OVA-pulsed DCs directly into the airways of naive animals results in not only OVA sensitization but also an ensuing TH2 response, eosinophilic airway inflammation, goblet cell hyperplasia, and bronchial hyperreactivity after rechallenge with OVA aerosol.9Lambrecht B.N. De Veerman M. Coyle A.J. Gutierrez-Ramos J.C. Thielemans K. Pauwels R.A. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation.J Clin Invest. 2000; 106: 551-559Crossref PubMed Google Scholar, 10Sung S. Rose C.E. Fu S.M. Intratracheal priming with ovalbumin- and ovalbumin 323-339 peptide-pulsed dendritic cells induces airway hyperresponsiveness, lung eosinophilia, goblet cell hyperplasia, and inflammation.J Immunol. 2001; 166: 1261-1271Crossref PubMed Google Scholar Antigen-pulsed DCs also have been shown to promote the development of allergic inflammation when administered intratracheally in primed mice, even in the absence of antigen aerosol.10Sung S. Rose C.E. Fu S.M. Intratracheal priming with ovalbumin- and ovalbumin 323-339 peptide-pulsed dendritic cells induces airway hyperresponsiveness, lung eosinophilia, goblet cell hyperplasia, and inflammation.J Immunol. 2001; 166: 1261-1271Crossref PubMed Google Scholar, 11van Rijt L.S. Jung S. Kleinjan A. Vos N. Willart M. Duez C. et al.In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma.J Exp Med. 2005; 201: 981-991Crossref PubMed Scopus (373) Google Scholar, 12Kuipers H. Soullie T. Hammad H. Willart M. Kool M. Hijdra D. et al.Sensitization by intratracheally injected dendritic cells is independent of antigen presentation by host antigen-presenting cells.J Leukoc Biol. 2009; 85: 64-70Crossref PubMed Scopus (10) Google Scholar Finally, it has been shown that depletion of DCs from OVA-sensitized mice abrogates aeroallergen-induced airway hyperreactivity and that repletion of these cells restores the asthma phenotype in these animals.11van Rijt L.S. Jung S. Kleinjan A. Vos N. Willart M. Duez C. et al.In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma.J Exp Med. 2005; 201: 981-991Crossref PubMed Scopus (373) Google Scholar, 13Lambrecht B.N. Salomon B. Klatzmann D. Pauwels R.A. Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice.J Immunol. 1998; 160: 4090-4097PubMed Google Scholar All of these observations together support critical roles for DCs in both the development and maintenance of allergen-induced airway inflammation and hyperreactivity in murine models. In evaluating the evidence for a DC-asthma association in human subjects, parallels can be made only for the first observation that numbers of airway DCs are increased in human subjects after allergen challenge. These studies are reviewed below in the "DC recruitment to the airway" section. DCs have been identified in dense networks throughout the epithelium of the respiratory tract, including the nose, nasopharynx, large conducting airways, bronchi, bronchioles, and alveolar interstitium.14Condon T.V. Sawyer R.T. Fenton M.J. Riches D.W. Lung dendritic cells at the innate-adaptive immune interface.J Leukoc Biol. 2011; 90: 883-895Crossref PubMed Scopus (17) Google Scholar, 15McWilliam A.S. Nelson D.J. Holt P.G. The biology of airway dendritic cells.Immunol Cell Biol. 1995; 73: 405-413Crossref PubMed Google Scholar, 16Sertl K. Takemura T. Tschachler E. Ferrans V.J. Kaliner M.A. Shevach E.M. Dendritic cells with antigen-presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura.J Exp Med. 1986; 163: 436-451Crossref PubMed Google Scholar, 17Gong J.L. McCarthy K.M. Telford J. Tamatani T. Miyasaka M. Schneeberger E.E. Intraepithelial airway dendritic cells: a distinct subset of pulmonary dendritic cells obtained by microdissection.J Exp Med. 1992; 175: 797-807Crossref PubMed Google Scholar, 18Fokkens W.J. Vroom T.M. Rijntjes E. Mulder P.G. CD-1 (T6), HLA-DR-expressing cells, presumably Langerhans cells, in nasal mucosa.Allergy. 1989; 44: 167-172Crossref PubMed Google Scholar, 19Holt P.G. Schon-Hegrad M.A. Localization of T cells, macrophages and dendritic cells in rat respiratory tract tissue: implications for immune function studies.Immunology. 1987; 62: 349-356PubMed Google Scholar Populations of DCs exist both above and beneath the basement membrane of the respiratory epithelium,20Schon-Hegrad M.A. Oliver J. McMenamin P.G. Holt P.G. Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways.J Exp Med. 1991; 173: 1345-1356Crossref PubMed Google Scholar positioning these cells as first responders to incoming antigens. Defining the division of labor between lung DC subsets in murine models has contributed to the current understanding of the role of DCs in the airway, especially how, on allergen inhalation, they contribute to the development of tolerance versus allergic inflammation.14Condon T.V. Sawyer R.T. Fenton M.J. Riches D.W. Lung dendritic cells at the innate-adaptive immune interface.J Leukoc Biol. 2011; 90: 883-895Crossref PubMed Scopus (17) Google Scholar, 21Lambrecht B.N. Hammad H. Biology of lung dendritic cells at the origin of asthma.Immunity. 2009; 31: 412-424Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 22GeurtsvanKessel C.H. Lambrecht B.N. Division of labor between dendritic cell subsets of the lung.Mucosal Immunol. 2008; 1: 442-450Crossref PubMed Scopus (81) Google Scholar Several lung DC subsets with distinct functions have been identified in specific anatomic locations.23von Garnier C. Filgueira L. Wikstrom M. Smith M. Thomas J.A. Strickland D.H. et al.Anatomical location determines the distribution and function of dendritic cells and other APCs in the respiratory tract.J Immunol. 2005; 175: 1609-1618Crossref PubMed Google Scholar Although there is significant overlap in the expression of DC surface proteins among these subsets, certain subsets, defined by unique surface marker profiles, have been shown to be particularly associated with allergic inflammatory responses. DC subsets in the murine lung can be broadly separated into 2 categories: conventional dendritic cells (cDCs), which express high levels of the integrin CD11c, and plasmacytoid dendritic cells (pDCs), which express Siglec-H, Ly6C, and B220 but low levels of CD11c. Importantly, the 3 DC subsets described in Table I have distinct anatomic locations and division of labor. The cDC subset can be further subdivided into the CD103+ cDC group and the CD11b+ cDC group. CD103 is an αE integrin that is highly expressed at mucosal sites. The first subset, CD103+ cDCs, is intimately associated with the respiratory epithelium. Here they project their dendritic extensions between epithelial cells, allowing them to directly sample airway luminal contents. This subset of lung DCs has been termed the "intraepithelial" subset. These cells express tight junction proteins, which allow them to anchor themselves within the epithelial cell layer. Enzyme activity of allergens, such as the cysteine protease of Der p 1 (Dermatophagoides pteronyssinus allergen), causes cleavage of epithelial tight junctions,24Wan H. Winton H.L. Soeller C. Tovey E.R. Gruenert D.C. Thompson P.J. et al.Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions.J Clin Invest. 1999; 104: 123-133Crossref PubMed Google Scholar providing a potential mechanism by which CD103+ DCs begin migration to lymph nodes, where they can transfer antigen to resident lymph node DCs.Table IMajor murine lung DC subsetsDC subsetSurface markersSpecialized functionAnatomic locationCD103+ cDCs "intraepithelial"CD11b−CD103+CD11c+Langerin+Tight junction proteins"Periscope" surveillance of airway luminal surface, antigen uptakeAssociated with epithelium of large conducting airways above basement membraneCD11b+ cDCsCD11b+CD103−CD11c+Efficient priming and restimulating effector CD4 T cells in lung; rich source of proinflammatory chemokines, attracting effector CD4 and CD8 cellsSubmucosa/lamina propria of conducting airways beneath basement membrane and lung parenchymapDCsSiglec-H, Ly6C, B220CD11cint, Gr-1intRole in inducing tolerance to inhaled antigens, induce regulatory T-cell development; secretion of type I IFNLarge conducting airways beneath basement membrane; lining alveolar septum Open table in a new tab A second lung DC subset is the CD11b+ cDC subset that resides beneath the basement membrane in conducting airways and lung parenchyma. This subset displays an efficient capacity for priming and restimulating effector CD4+ T cells in the lung.11van Rijt L.S. Jung S. Kleinjan A. Vos N. Willart M. Duez C. et al.In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma.J Exp Med. 2005; 201: 981-991Crossref PubMed Scopus (373) Google Scholar, 25del Rio M.L. Rodriguez-Barbosa J.I. Kremmer E. Forster R. CD103- and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells.J Immunol. 2007; 178: 6861-6866Crossref PubMed Google Scholar CD11b+ DCs play a major role in influencing allergic inflammation by providing a rich source of proinflammatory chemokines, such as TNF-α and thymus and activation-regulated chemokine (TARC)/CCL-17.11van Rijt L.S. Jung S. Kleinjan A. Vos N. Willart M. Duez C. et al.In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma.J Exp Med. 2005; 201: 981-991Crossref PubMed Scopus (373) Google Scholar, 26Sung S.S. Fu S.M. Rose Jr., C.E. Gaskin F. Ju S.T. Beaty S.R. A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins.J Immunol. 2006; 176: 2161-2172Crossref PubMed Google Scholar Secretion of these chemokines results in attraction of TH2 CD4+ and CD8+ effector T cells to the lung, a critical step in the development of allergic inflammation. Although cDCs contribute to the development of tolerance to inhaled allergens,27Akbari O. DeKruyff R.H. Umetsu D.T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen.Nat Immunol. 2001; 2: 725-731Crossref PubMed Scopus (902) Google Scholar tolerance is particularly dependent on the presence of a third lung DC subset, pDCs. After taking up inhaled antigens, including allergens, pDCs have the capacity to drive the development of regulatory T cells, a cell type critical to the development of tolerance to foreign antigens.28de Heer H.J. Hammad H. Soullie T. Hijdra D. Vos N. Willart M.A. et al.Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.J Exp Med. 2004; 200: 89-98Crossref PubMed Scopus (489) Google Scholar Evidence that pDCs provide intrinsic protection against inflammatory responses to harmless antigen has been established in murine models of OVA-induced asthma.28de Heer H.J. Hammad H. Soullie T. Hijdra D. Vos N. Willart M.A. et al.Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.J Exp Med. 2004; 200: 89-98Crossref PubMed Scopus (489) Google Scholar, 29Kool M. van Nimwegen M. Willart M.A. Muskens F. Boon L. Smit J.J. et al.An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation.J Immunol. 2009; 183: 1074-1082Crossref PubMed Scopus (58) Google Scholar de Heer et al28de Heer H.J. Hammad H. Soullie T. Hijdra D. Vos N. Willart M.A. et al.Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.J Exp Med. 2004; 200: 89-98Crossref PubMed Scopus (489) Google Scholar demonstrated that depletion of pDCs with either anti–Gr-1 antibody or the pDC-specific antibody 120G830Asselin-Paturel C. Brizard G. Pin J.J. Briere F. Trinchieri G. Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody.J Immunol. 2003; 171: 6466-6477Crossref PubMed Google Scholar during OVA inhalation resulted in the development of cardinal features of asthma, including airway eosinophilia and TH2 cytokine production. Moreover, adoptive transfer of pDCs into mice before OVA sensitization prevented disease in this model. A possible mechanism by which pDCs inhibit allergic airway inflammation lies in the capacity of pDCs to release massive concentrations of IFN-α on stimulation with viruses or certain TLR agonists.31Liu Y.J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.Annu Rev Immunol. 2005; 23: 275-306Crossref PubMed Scopus (847) Google Scholar It should be emphasized that this mechanism has been demonstrated in human studies. Recent in vitro studies of human circulating naive CD4+ T cells revealed that IFN-α blocks TH2 development through suppression of GATA-3, the primary TH2 transcription factor. In addition, IFN-α inhibited secretion of IL-4, IL-5, and IL-14 from committed TH2 cells.32Huber J.P. Ramos H.J. Gill M.A. Farrar J.D. Cutting edge: Type I IFN reverses human Th2 commitment and stability by suppressing GATA3.J Immunol. 2010; 185: 813-817Crossref PubMed Scopus (40) Google Scholar Thus pDCs might exert inhibitory effects on the development of TH2 inflammatory responses in vivo through their secretion of IFN-α. This aspect of pDC biology as it relates to asthma is discussed in more detail in the subsequent section entitled "Relationships among viruses, IFN-α, IgE, DCs, and asthma." The above scheme represents a simplified view of lung DC subset functions; division of labor and specialized functions can be further subdivided based on location in the airways versus lung parenchyma.33Wikstrom M.E. Stumbles P.A. Mouse respiratory tract dendritic cell subsets and the immunological fate of inhaled antigens.Immunol Cell Biol. 2007; 85: 182-188PubMed Google Scholar A greater delineation of the precise functions of these distinct lung DC subsets will provide opportunities for the development of potential new therapies targeting DC-driven development of allergic inflammation. In human subjects knowledge regarding lung DC subsets is not as complete. As in mice, DCs can be broadly divided into 2 major groups: myeloid dendritic cells (mDCs; also referred to as "conventional" DCs) and pDCs.14Condon T.V. Sawyer R.T. Fenton M.J. Riches D.W. Lung dendritic cells at the innate-adaptive immune interface.J Leukoc Biol. 2011; 90: 883-895Crossref PubMed Scopus (17) Google Scholar Expression of the integrin CD11c combined with expression of a set of blood dendritic cell antigen (BDCA) antibodies has recently been used to define/differentiate mDC and pDC subsets (Table II).34Demedts I.K. Brusselle G.G. Vermaelen K.Y. Pauwels R.A. Identification and characterization of human pulmonary dendritic cells.Am J Respir Cell Mol Biol. 2005; 32: 177-184Crossref PubMed Scopus (129) Google Scholar, 35Masten B.J. Olson G.K. Tarleton C.A. Rund C. Schuyler M. Mehran R. et al.Characterization of myeloid and plasmacytoid dendritic cells in human lung.J Immunol. 2006; 177: 7784-7793Crossref PubMed Google Scholar, 36Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (69) Google Scholar, 37Lommatzsch M. Bratke K. Bier A. Julius P. Kuepper M. Luttmann W. et al.Airway dendritic cell phenotypes in inflammatory diseases of the human lung.Eur Respir J. 2007; 30: 878-886Crossref PubMed Scopus (39) Google Scholar mDCs can be further subdivided based on the expression of surface BDCA1 and BDCA3: type 1 mDCs express BDCA1 (CD1c), and type 2 mDCs express BDCA3 (CD141).34Demedts I.K. Brusselle G.G. Vermaelen K.Y. Pauwels R.A. Identification and characterization of human pulmonary dendritic cells.Am J Respir Cell Mol Biol. 2005; 32: 177-184Crossref PubMed Scopus (129) Google ScholarTable IIHuman lung DC subsetsDC subsetSurface markersExamples of studies identifying DCs in human lungmDCs (type 1)CD11c+BDCA1+ (CD1c)MHC class II (HLA-DR)+•Demedts et al34Demedts I.K. Brusselle G.G. Vermaelen K.Y. Pauwels R.A. Identification and characterization of human pulmonary dendritic cells.Am J Respir Cell Mol Biol. 2005; 32: 177-184Crossref PubMed Scopus (129) Google Scholar: 3 subsets in digests of normal lung specimens:1.HLA-DR+CD11c+BDCA1+ mDC subset2.HLA-DR+CD11c+BDCA3+ mDC subset3.CD123+BDCA2+ pDC subsetmDCs (type 2)CD11c+BDCA3+ (CD141)MHC class II (HLA-DR)+•Masten et al35Masten B.J. Olson G.K. Tarleton C.A. Rund C. Schuyler M. Mehran R. et al.Characterization of myeloid and plasmacytoid dendritic cells in human lung.J Immunol. 2006; 177: 7784-7793Crossref PubMed Google Scholar: CD1c+CD11c+CD14−HLA-DR+ mDCs and CD123+CD11c−CD14−HLA-DR+ pDCs (BDCA2+ pDCs identified) in normal lung specimens•Bratke et al36Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (69) Google Scholar: CD11c+HLA-DR+ mDCs and CD123+HLA-DR+ pDCs in BALF after allergen challengepDCsCD123+, CD11c−BDCA2+, BDCA4+MHC class II (HLA-DR)+ILT7+•Lommatzsch et al37Lommatzsch M. Bratke K. Bier A. Julius P. Kuepper M. Luttmann W. et al.Airway dendritic cell phenotypes in inflammatory diseases of the human lung.Eur Respir J. 2007; 30: 878-886Crossref PubMed Scopus (39) Google Scholar: CD1a+CD11c+HLA-DR+ mDCs, CD1a−CD11c+HLA-DR+ mDCs, and CD123+HLA-DR+ pDCs in BALF from healthy and disease states; evidence of influence of pulmonary inflammatory diseases on DC airway recruitment and phenotype Open table in a new tab CD1a expression also delineates another subset of mDCs and has been demonstrated on human lung DCs as well. CD11c+CD1a+ DCs can differentiate to Langerhans cells at epithelial surfaces, whereas CD11c+CD1a− mDCs replenish mDCs within interstitial compartments.38Gogolak P. Rethi B. Szatmari I. Lanyi A. Dezso B. Nagy L. et al.Differentiation of CD1a- and CD1a+ monocyte-derived dendritic cells is biased by lipid environment and PPARgamma.Blood. 2007; 109: 643-652Crossref PubMed Scopus (59) Google Scholar Demedts et al34Demedts I.K. Brusselle G.G. Vermaelen K.Y. Pauwels R.A. Identification and characterization of human pulmonary dendritic cells.Am J Respir Cell Mol Biol. 2005; 32: 177-184Crossref PubMed Scopus (129) Google Scholar identified CD1a+ mDCs in human lung tissues; interestingly, these DCs were most abundant in the epithelium, whereas the CD1c+ mDCs were found more frequently in the submucosa. pDCs express BDCA2 (CD303), CD123 (the IL-3 receptor), and immunoglobulin-like transcript 7 (ILT7). Both mDCs and pDCs have been identified in human lung tissue; examples of studies demonstrating this are shown in Table II.34Demedts I.K. Brusselle G.G. Vermaelen K.Y. Pauwels R.A. Identification and characterization of human pulmonary dendritic cells.Am J Respir Cell Mol Biol. 2005; 32: 177