Initiation of Lung Immunity: The Afferent Limb and the Role of Dendritic Cells

The lung is the largest epithelial surface in the body and constitutes a major portal of entry for microorganisms. Dendritic cells (DCs) are bone marrow-derived cells that populate the respiratory tract from the nasal mucosa to the lung pleura. DCs are dexterous cells playing a role in both the innate and the adaptive immune responses. DCs can respond to dangers in the lung by immediately generating protective cytokines that stimulate natural killer (NK) cells to produce cytokines and kill targets. Direct (by pathogen recognition receptors) and indirect (by inflammatory cytokines) recognition of the infectious agent can also trigger signaling pathways in the DCs that activate an integrated developmental program called maturation, which transforms DCs into efficient antigen-presenting cells (APCs) for naive T cell stimulation. Furthermore, DCs play a role in generating effector B cells in the lymph nodes draining the lung. This review focuses on how DCs sense the health of the lung and translate messages regarding the lung microenvironment to cells of the innate and adaptive immune response to initiate effector functions to clear an invading microorganism [T helper 1 (Th1) or Th2 response] or generate tolerance [T regulatory (Tr), anergy, or deletion] to inhaled antigen when no danger is sensed.

KEYWORDS

Dendritic cells - antigen-presenting cells - afferent - adaptive immunity

REFERENCES

• 1 Steinman R M, Hawiger D, Nussenzweig M C. Tolerogenic dendritic cells.  Annu Rev Immunol. 2003;  21 685-711
• 2 Diamond G, Legarda D, Ryan L K. The innate immune response of the respiratory epithelium.  Immunol Rev. 2000;  173 27-38
• 3 Medzhitov R, Janeway Jr C. Innate immune recognition: mechanisms and pathways.  Immunol Rev. 2000;  173 89-97
• 4 Zhang P, Summer W R, Bagby G J, Nelson S. Innate immunity and pulmonary host defense.  Immunol Rev. 2000;  173 39-51
• 5 van Haarst J M, Verhoeven G T, de Wit H J, Hoogsteden H C, Debets R, Drexhage H A. CD1a⁺ and CD1a^- accessory cells from human bronchoalveolar lavage differ in allostimulatory potential and cytokine production.  Am J Respir Cell Mol Biol. 1996;  15 752-759
• 6 Holt P G, Haining S, Nelson D J, Sedgwick J D. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways.  J Immunol. 1994;  153 256-261
• 7 Xia W, Pinto C E, Kradin R L. The antigen-presenting activities of Ia⁺ dendritic cells shift dynamically from lung to lymph node after an airway challenge with soluble antigen.  J Exp Med. 1995;  181 1275-1283
• 8 Constant S L, Brogdon J L, Piggott D A et al.. Resident lung antigen-presenting cells have the capacity to promote Th2 T cell differentiation in situ.  J Clin Invest. 2002;  110 1441-1448
• 9 Lipscomb M F, Huffnagle G B, Lovchik J A, Lyons C R, Pollard A M, Yates J L. The role of T lymphocytes in pulmonary microbial defense mechanisms.  Arch Pathol Lab Med. 1993;  117 1225-1232
• 10 Lipscomb M F, Masten B J. Dendritic cells: immune regulators in health and disease.  Physiol Rev. 2002;  82 97-130
• 11 Vermaelen K Y, Carro-Muino I, Lambrecht B N, Pauwels R A. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes.  J Exp Med. 2001;  193 51-60
• 12 Byersdorfer C A, Chaplin D D. Visualization of early APC/T cell interactions in the mouse lung following intranasal challenge.  J Immunol. 2001;  167 6756-6764
• 13 Mellman I, Steinman R M. Dendritic cells: specialized and regulated antigen processing machines.  Cell. 2001;  106 255-258
• 14 Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells.  Annu Rev Immunol. 2002;  20 621-667
• 15 Moody D B, Porcelli S A. Intracellular pathways of CD1 antigen presentation.  Nat Rev Immunol. 2003;  3 11-22
• 16 Masten B J, Yates J L, Pollard Koga A M, Lipscomb M F. Characterization of accessory molecules in murine lung dendritic cell function: roles for CD80, CD86, CD54, and CD40L.  Am J Respir Cell Mol Biol. 1997;  16 335-342
• 17 Masten B J, Lipscomb M F. Comparison of lung dendritic cells and B cells in stimulating naive antigen-specific T cells.  J Immunol. 1999;  162 1310-1317
• 18 Kadowaki N, Ho S, Antonenko S et al.. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens.  J Exp Med. 2001;  194 863-869
• 19 Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells.  Eur J Immunol. 2001;  31 3388-3393
• 20 Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity.  Nat Rev Immunol. 2003;  3 133-146
• 21 Ferlazzo G, Tsang M L, Moretta L, Melioli G, Steinman R M, Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells.  J Exp Med. 2002;  195 343-351
• 22 Fernandez N C, Flament C, Crepineau F, Angevin E, Vivier E, Zitvogel L. Dendritic cells (DC) promote natural killer (NK) cell functions: dynamics of the human DC/NK cell cross talk.  Eur Cytokine Netw. 2002;  13 17-27
• 23 Ferlazzo G, Morandi B, D'Agostino A et al.. The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells.  Eur J Immunol. 2003;  33 306-313
• 24 Dieu M C, Vanbervliet B, Vicari A et al.. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites.  J Exp Med. 1998;  188 373-386
• 25 Cyster J G. Chemokines and cell migration in secondary lymphoid organs.  Science. 1999;  286 2098-2102
• 26 Cavanagh L L, Von Andrian U H. Travellers in many guises: the origins and destinations of dendritic cells.  Immunol Cell Biol. 2002;  80 448-462
• 27 Akbari O, DeKruyff R H, Umetsu D T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen.  Nat Immunol. 2001;  2 725-731
• 28 Bozza S, Gaziano R, Spreca A et al.. Dendritic cells transport conidia and hyphae of Aspergillus fumigatus from the airways to the draining lymph nodes and initiate disparate Th responses to the fungus.  J Immunol. 2002;  168 1362-1371
• 29 Akbari O, Freeman G J, Meyer E H et al.. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.  Nat Med. 2002;  8 1024-1032
• 30 Eisenbarth S C, Piggott D A, Huleatt J W, Visintin I, Herrick C A, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.  J Exp Med. 2002;  196 1645-1651
• 31 Lambrecht 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 4090-4097
• 32 Swain S L, Weinberg A D, English M, Huston G. IL-4 directs the development of Th2-like helper effectors.  J Immunol. 1990;  145 3796-3806
• 33 Ruedl C, Bachmann M F, Kopf M. The antigen dose determines T helper subset development by regulation of CD40 ligand.  Eur J Immunol. 2000;  30 2056-2064
• 34 Langenkamp A, Messi M, Lanzavecchia A, Sallusto F. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells.  Nat Immunol. 2000;  1 311-316
• 35 Kikuchi K, Yanagawa Y, Aranami T, Iwabuchi C, Iwabuchi K, Onoe K. Tumour necrosis factor-alpha but not lipopolysaccharide enhances preference of murine dendritic cells for Th2 differentiation.  Immunology. 2003;  108 42-49
• 36 Boonstra A, Asselin-Paturel C, Gilliet M et al.. Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation.  J Exp Med. 2003;  197 101-109
• 37 Sharpe A H, Freeman G J. The B7-CD28 superfamily.  Nat Rev Immunol. 2002;  2 116-126
• 38 Geijtenbeek T B, Krooshoop D J, Bleijs D A et al.. DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking.  Nat Immunol. 2000;  1 353-357
• 39 Medzhitov R. Toll-like receptors and innate immunity.  Nat Rev Immunol. 2001;  1 135-145
• 40 Sabroe I, Parker L C, Wilson A G, Whyte M K, Dower S K. Toll-like receptors: their role in allergy and non-allergic inflammatory disease.  Clin Exp Allergy. 2002;  32 984-989
• 41 Lien E, Ingalls R R. Toll-like receptors.  Crit Care Med. 2002;  30 S1-11
• 42 Liu T, Matsuguchi T, Tsuboi N, Yajima T, Yoshikai Y. Differences in expression of toll-like receptors and their reactivities in dendritic cells in BALB/c and C57BL/6 mice.  Infect Immun. 2002;  70 6638-6645
• 43 Stumbles P A, Thomas J A, Pimm C L et al.. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity.  J Exp Med. 1998;  188 2019-2031
• 44 Stumbles P A, Strickland D H, Pimm C L et al.. Regulation of dendritic cell recruitment into resting and inflamed airway epithelium: use of alternative chemokine receptors as a function of inducing stimulus.  J Immunol. 2001;  167 228-234
• 45 Beg A A. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses.  Trends Immunol. 2002;  23 509-512
• 46 Power C A, Church D J, Meyer A et al.. Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells.  J Exp Med. 1997;  186 825-835
• 47 Adema G J, Hartgers F, Verstraten R et al.. A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells.  Nature. 1997;  387 713-717
• 48 Yanagawa Y, Onoe K. CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant upregulation of Cdc42 and Rac activities.  Blood. 2003;  101 4923-4929
• 49 Holt P G, Schon-Hegrad M A, Phillips M J, McMenamin P G. Ia-positive dendritic cells form a tightly meshed network within the human airway epithelium.  Clin Exp Allergy. 1989;  19 597-601
• 50 Holt P G, Schon-Hegrad M A, Oliver J, Holt B J, McMenamin P G. A contiguous network of dendritic antigen-presenting cells within the respiratory epithelium.  Int Arch Allergy Appl Immunol. 1990;  91 155-159
• 51 Sertl 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;  163 436-451
• 52 Suda T, McCarthy K, Vu Q, McCormack J, Schneeberger E E. Dendritic cell precursors are enriched in the vascular compartment of the lung.  Am J Respir Cell Mol Biol. 1998;  19 728-737
• 53 Legge K L, Braciale T J. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection.  Immunity. 2003;  18 265-277
• 54 Lipscomb M F, Pollard A M, Yates J L. A role for TGF-beta in the suppression by murine bronchoalveolar cells of lung dendritic cell initiated immune responses.  Reg Immunol. 1993;  5 151-157
• 55 Bilyk N, Holt P G. Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations.  Immunology. 1995;  86 231-237
• 56 Kradin R, MacLean J, Duckett S, Schneeberger E E, Waeber C, Pinto C. Pulmonary response to inhaled antigen: neuroimmune interactions promote the recruitment of dendritic cells to the lung and the cellular immune response to inhaled antigen.  Am J Pathol. 1997;  150 1735-1743
• 57 Lambrecht B N, Germonpre P R, Everaert E G et al.. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation.  Eur J Immunol. 1999;  29 3815-3825
• 58 Dzionek A, Fuchs A, Schmidt P et al.. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood.  J Immunol. 2000;  165 6037-6046
• 59 Dzionek A, Sohma Y, Nagafune J et al.. BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction.  J Exp Med. 2001;  194 1823-1834
• 60 Jahnsen F L, Moloney E D, Hogan T, Upham J W, Burke C M, Holt P G. Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge.  Thorax. 2001;  56 823-826
• 61 Astori M, von Garnier C, Kettner A, Dufour N, Corradin G, Spertini F. Inducing tolerance by intranasal administration of long peptides in naive and primed CBA/J mice.  J Immunol. 2000;  165 3497-3505
• 62 Constant S L, Lee K S, Bottomly K. Site of antigen delivery can influence T cell priming: pulmonary environment promotes preferential Th2-type differentiation.  Eur J Immunol. 2000;  30 840-847
• 63 Jones H P, Hodge L M, Fujihashi K, Kiyono H, McGhee J R, Simecka J W. The pulmonary environment promotes Th2 cell responses after nasal-pulmonary immunization with antigen alone, but Th1 responses are induced during instances of intense immune stimulation.  J Immunol. 2001;  167 4518-4526
• 64 Herrick C A, MacLeod H, Glusac E, Tigelaar R E, Bottomly K. Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4.  J Clin Invest. 2000;  105 765-775
• 65 McGuirk P, McCann C, Mills K H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis.  J Exp Med. 2002;  195 221-231
• 66 Lagranderie M, Balazuc A M, Abolhassani M et al.. Development of mixed Th1/Th2 type immune response and protection against Mycobacterium tuberculosis after rectal or subcutaneous immunization of newborn and adult mice with Mycobacterium bovis BCG.  Scand J Immunol. 2002;  55 293-303
• 67 McWilliam A S, Nelson D, Thomas J A, Holt P G. Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces.  J Exp Med. 1994;  179 1331-1336
• 68 Vu Q, McCarthy K M, McCormack J M, Schneeberger E E. Lung dendritic cells are primed by inhaled particulate antigens, and retain MHC class II/antigenic peptide complexes in hilar lymph nodes for a prolonged period of time.  Immunology. 2002;  105 488-498
• 69 MacLean J A, Xia W, Pinto C E, Zhao L, Liu H W, Kradin R L. Sequestration of inhaled particulate antigens by lung phagocytes: a mechanism for the effective inhibition of pulmonary cell-mediated immunity.  Am J Pathol. 1996;  148 657-666
• 70 Bauman S K, Huffnagle G B, Murphy J W. Effects of tumor necrosis factor alpha on dendritic cell accumulation in lymph nodes draining the immunization site and the impact on the anticryptococcal cell-mediated immune response.  Infect Immun. 2003;  71 68-74
• 71 Usherwood E J, Hogg T L, Woodland D L. Enumeration of antigen-presenting cells in mice infected with Sendai virus.  J Immunol. 1999;  162 3350-3355
• 72 Lambrecht B N, Pauwels R A, Fazekas De St Groth B. Induction of rapid T cell activation, division, and recirculation by intratracheal injection of dendritic cells in a TCR transgenic model.  J Immunol. 2000;  164 2937-2946
• 73 McWilliam A S, Napoli S, Marsh A M et al.. Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli.  J Exp Med. 1996;  184 2429-2432
• 74 Lin C L, Suri R M, Rahdon R A, Austyn J M, Roake J A. Dendritic cell chemotaxis and transendothelial migration are induced by distinct chemokines and are regulated on maturation.  Eur J Immunol. 1998;  28 4114-4122
• 75 Ying S, Meng Q, Zeibecoglou K et al.. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics.  J Immunol. 1999;  163 6321-6329
• 76 Nakano H, Yanagita M, Gunn M D. CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells.  J Exp Med. 2001;  194 1171-1178
• 77 Sonoda K H, Faunce D E, Taniguchi M, Exley M, Balk S, Stein-Streilein J. NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance.  J Immunol. 2001;  166 42-50
• 78 Chen H, Paul W E. Cultured NK1.1+ CD4+ T cells produce large amounts of IL-4 and IFN-gamma upon activation by anti-CD3 or CD1.  J Immunol. 1997;  159 2240-2249
• 79 Dubois B, Bridon J M, Fayette J et al.. Dendritic cells directly modulate B cell growth and differentiation.  J Leukoc Biol. 1999;  66 224-230
• 80 Litinskiy M B, Nardelli B, Hilbert D M et al.. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL.  Nat Immunol. 2002;  3 822-829