International Journal of Hematology

, Volume 81, Issue 3, pp 197–203 | Cite as

Dendritic Cells: Sentinels of Immunity and Tolerance

  • Jan Kubach
  • Christian Becker
  • Edgar Schmitt
  • Kerstin Steinbrink
  • Eva Huter
  • Andrea Tuettenberg
  • Helmut JonuleitEmail author
Progress in Hematology


The induction of effective antigen-specific T-cell immunity to pathogens without the initiation of autoimmunity has evolved as a sophisticated and highly balanced immunoregulatory mechanism. This mechanism assures the generation of antigen-specific effector cells as well as the induction and maintenance of antigen-specific tolerance to self-structures of the body. As professional antigen-presenting cells of the immune system, dendritic cells (DC) are ideally positioned throughout the entire body and equipped with a unique capability to transport antigens from the periphery to lymphoid tissues. There is growing evidence that DC, besides their well-known immunostimulatory properties, also induce and regulate T-cell tolerance in the periphery. This regulatory function of DC is strictly dependent on their different stages of maturation and activation. Additionally, immunosuppressive agents and cytokines further influence the functions of maturing DC. The regulatory properties of DC include induction of T-cell anergy, apoptosis, and the generation of T-cells with regulatory capacities. This brief review summarizes the current knowledge about the immunoregulatory role of DC as guardians for the induction of T-cell immunity and tolerance.

Key words

Dendritic cells Tolerance Sentinels Maturation Regulatory T-cells 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–252.CrossRefPubMedGoogle Scholar
  2. 2.
    Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.CrossRefPubMedGoogle Scholar
  3. 3.
    Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H. Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol. 2002;80:477–483.CrossRefPubMedGoogle Scholar
  4. 4.
    Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J. Exp Med. 1985;161:526–546.CrossRefPubMedGoogle Scholar
  5. 5.
    Hart DN, Fabre JW. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med. 1981;154:347–361.CrossRefPubMedGoogle Scholar
  6. 6.
    Vermaelen KY, Carro-Muino I, Lambrecht BN, Pauwels RA. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J Exp Med. 2001;193:51–60.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Huang FP, Platt N, Wykes M, et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med. 2000;191:435–444.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Schon-Hegrad MA, Oliver J, McMenamin PG, Holt PG. 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; 173:1345–1356.CrossRefPubMedGoogle Scholar
  9. 9.
    Edwards AD, Diebold SS, Slack EM, et al. Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol. 2003;33:827–833.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Shortman K. Burnet oration: dendritic cells: multiple subtypes, multiple origins, multiple functions. Immunol Cell Biol. 2000;78:161–165.CrossRefPubMedGoogle Scholar
  12. 12.
    Greaves DR, Wang W, Dairaghi DJ, et al. CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3a and is highly expressed in human dendritic cells. J Exp Med. 1997; 186:837–844.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Matzinger P. An innate sense of danger. Semin Immunol. 1998;10:399–415.CrossRefPubMedGoogle Scholar
  14. 14.
    Geijtenbeek TB, van Vliet SJ, Engering A, ’t Hart BA, van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol. 2004;22:33–54.CrossRefPubMedGoogle Scholar
  15. 15.
    Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell. 2001;106:255–258.CrossRefPubMedGoogle Scholar
  16. 16.
    Kamath AT, Pooley J, O’Keeffe MA, et al. The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J Immunol. 2000;165:6762–6770.CrossRefPubMedGoogle Scholar
  17. 17.
    Ohl L, Mohaupt M, Czeloth N, et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity. 2004;21:279–288.CrossRefPubMedGoogle Scholar
  18. 18.
    Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med. 2000;191:411–416.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic cell responses to pathogens and their components. Science. 2001;294:870–875.CrossRefPubMedGoogle Scholar
  20. 20.
    Janeway CA Jr, Medzhitov R. Introduction: the role of innate immunity in the adaptive immune response. Semin Immunol. 1998; 10:349–350.CrossRefPubMedGoogle Scholar
  21. 21.
    Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–995.CrossRefPubMedGoogle Scholar
  22. 22.
    Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–2088.CrossRefPubMedGoogle Scholar
  23. 23.
    Tsuji S, Matsumoto M,Takeuchi O, et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin: involvement of Toll-like receptors. Infect Immun. 2000;68:6883–6890.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–745.CrossRefPubMedGoogle Scholar
  25. 25.
    Bauer S, Kirschning CJ, Hacker H, et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc NatlAcad Sci USA. 2001;98:9237–9242.CrossRefGoogle Scholar
  26. 26.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature. 2001;413:732–738.CrossRefPubMedGoogle Scholar
  27. 27.
    Inaba K, Turley S, Yamaide F, et al. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med. 1998;188:2163–2173.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sallusto F, Schaerli P, Loetscher P, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998;28:2760–2769.CrossRefPubMedGoogle Scholar
  29. 29.
    Kalinski P, Hilkens CM, Wierenga EA, Kapsenberg ML. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today. 1999;20:561–567.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    MacDonald AS, Straw AD, Dalton NM, Pearce EJ. Cutting edge: Th2 response induction by dendritic cells: a role for CD40. J Immunol. 2002;168:537–540.CrossRefPubMedGoogle Scholar
  32. 32.
    Gagliardi MC, Sallusto F, Marinaro M, Langenkamp A, Lanzavecchia A, De Magistris MT. Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming. Eur J Immunol. 2000;30:2394–2403.CrossRefPubMedGoogle Scholar
  33. 33.
    Shevach EM, McHugh RS, Piccirillo CA, Thornton AM. Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev. 2001;182:58–67.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001;182:18–32.CrossRefPubMedGoogle Scholar
  35. 35.
    Weiner HL. Induction and mechanism of action of transforming growth factor-β-secreting Th3 regulatory cells. Immunol Rev. 2001; 182:207–214.CrossRefGoogle Scholar
  36. 36.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001;182:68–79.CrossRefGoogle Scholar
  37. 37.
    Groux H, O’Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997; 389:737–742.CrossRefGoogle Scholar
  38. 38.
    Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature. 2003;421:388–392.CrossRefGoogle Scholar
  39. 39.
    Inobe J, Slavin AJ, Komagata Y, Chen Y, Liu L, Weiner HL. IL-4 is a differentiation factor for transforming growth factor-β secreting Th3 cells and oral administration of IL-4 enhances oral tolerance in experimental allergic encephalomyelitis. Eur J Immunol. 1998; 28:2780–2790.CrossRefGoogle Scholar
  40. 40.
    Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285–1294.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med. 2001;193:1303–1310.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ng WF, Duggan PJ, Ponchel F, et al. Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood. 2001; 98:2736–2744.CrossRefPubMedGoogle Scholar
  43. 43.
    Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol. 1998;10:371–378.CrossRefPubMedGoogle Scholar
  44. 44.
    Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996;183:2669–2674.CrossRefPubMedGoogle Scholar
  45. 45.
    Fuss IJ, Boirivant M, Lacy B, Strober W. The interrelated roles of TGF-β and IL-10 in the regulation of experimental colitis. J. Immunol. 2002;168:900–908.CrossRefPubMedGoogle Scholar
  46. 46.
    Stassen M, Fondel S, Bopp T, et al. Human CD25+ regulatory T cells: two subsets defined by the integrins α4β7 or α4β1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol. 2004; 34:1303–1311.CrossRefPubMedGoogle Scholar
  47. 47.
    Coates PT, Colvin BL, Hackstein H,Thomson AW. Manipulation of dendritic cells as an approach to improved outcomes in transplantation. Expert Rev Mol Med. 2002;2002:1–21.Google Scholar
  48. 48.
    Kronin V, Vremec D, Winkel K, et al. Are CD8+ dendritic cells (DC) veto cells? The role of CD8 on DC in DC development and in the regulation of CD4 and CD8 T cell responses. Int Immunol. 1997;9:1061–1064.CrossRefPubMedGoogle Scholar
  49. 49.
    Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med. 2000;192:1213–1222.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med. 2001;193:233–238.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Jonuleit H, Adema G, Schmitt E. Immune regulation by regulatory T cells: implications for transplantation. Transpl Immunol. 2003;11:267–276.CrossRefPubMedGoogle Scholar
  52. 52.
    Mahnke K, Qian Y, Knop J, Enk AH. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood. 2003;101:4862–4869.CrossRefPubMedGoogle Scholar
  53. 53.
    Witsch EJ, Peiser M, Hutloff A, et al. ICOS and CD28 reversely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells. Eur J Immunol. 2002;32:2680–2686.CrossRefPubMedGoogle Scholar
  54. 54.
    Akbari O, Freeman GJ, Meyer EH, 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.CrossRefPubMedGoogle Scholar
  55. 55.
    Lagaraine C, Lebranchu Y. Effects of immunosuppressive drugs on dendritic cells and tolerance induction. Transplantation. 2003; 75(suppl):37S-42S.CrossRefPubMedGoogle Scholar
  56. 56.
    de Jong EC, Vieira PL, Kalinski P, Kapsenberg ML. Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3. J Leukoc Biol. 1999;66:201–204.CrossRefPubMedGoogle Scholar
  57. 57.
    Penna G, Adorini L. 1α,25-Dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000;164:2405–2411.CrossRefPubMedGoogle Scholar
  58. 58.
    Piemonti L, Monti P, Sironi M, et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol. 2000;164:4443–4451.CrossRefPubMedGoogle Scholar
  59. 59.
    Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol. 1997;159:4772–4780.PubMedGoogle Scholar
  60. 60.
    Steinbrink K, Jonuleit H, Muller G, Schuler G, Knop J, Enk AH. Interleukin-10-treated human dendritic cells induce a melanoma- antigen-specific anergy in CD8+ T cells resulting in a failure to lyse tumor cells. Blood. 1999;93:1634–1642.PubMedGoogle Scholar
  61. 61.
    Bellinghausen I, Brand U, Steinbrink K, Enk AH, Knop J, Saloga J. Inhibition of human allergic T-cell responses by IL-10-treated dendritic cells: differences from hydrocortisone-treated dendritic cells. J Allergy Clin Immunol. 2001;108:242–249.CrossRefPubMedGoogle Scholar
  62. 62.
    Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH. CD4+ and CD8+ anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood. 2002;99:2468–2476.CrossRefPubMedGoogle Scholar
  63. 63.
    Kubsch S, Graulich E, Knop J, Steinbrink K. Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1. Eur J Immunol. 2003;33:1988–1997.CrossRefPubMedGoogle Scholar
  64. 64.
    Thornton AM, She vach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting inter- leukin 2 production. J Exp Med. 1998;188:287–296.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol. 2001;166:3008–3018.CrossRefPubMedGoogle Scholar
  66. 66.
    Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen- dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp Med. 2003;198:249–258.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    George TC, Bilsborough J, Viney JL, Norment AM. High antigen dose and activated dendritic cells enable Th cells to escape regulatory T cell-mediated suppression in vitro. Eur J Immunol. 2003;33:502–511.CrossRefPubMedGoogle Scholar
  68. 68.
    Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science. 2003;299:1033–1036.CrossRefPubMedGoogle Scholar
  69. 69.
    Yamazaki S, Iyoda T, Tarbell K, et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med. 2003;198:235–247.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12:431–440.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2005

Authors and Affiliations

  • Jan Kubach
    • 1
  • Christian Becker
    • 1
  • Edgar Schmitt
    • 2
  • Kerstin Steinbrink
    • 1
  • Eva Huter
    • 1
  • Andrea Tuettenberg
    • 1
  • Helmut Jonuleit
    • 1
    Email author
  1. 1.Department of DermatologyUniversity of MainzMainzGermany
  2. 2.Institute of ImmunologyUniversity of MainzMainzGermany

Personalised recommendations