Skip to main content

Advertisement

SpringerLink
Log in

Dendritic cells as gatekeepers of tolerance

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory T cells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Geissmann F et al. (2010) Development of monocytes, macrophages, and dendritic cells. Science 327(5966):656–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Naik SH et al. (2007) Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 8(11):1217–1226

    Article  CAS  PubMed  Google Scholar 

  3. Sela U et al. (2011) Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice. J Exp Med 208(12):2489–2496

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bogunovic M et al. (2009) Origin of the lamina propria dendritic cell network. Immunity 31(3):513–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ginhoux F et al. (2009) The origin and development of nonlymphoid tissue CD103+ DCs. J Exp Med 206(13):3115–3130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu K et al. (2009) In vivo analysis of dendritic cell development and homeostasis. Science 324(5925):392–397

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Merad M et al. (2013) The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31:563–604

    Article  CAS  PubMed  Google Scholar 

  8. Colonna M, Trinchieri G, Liu YJ (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5(12):1219–1226

    Article  CAS  PubMed  Google Scholar 

  9. Reizis B et al. (2011) Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol 29:163–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nakano H, Yanagita M, Gunn MD (2001) CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med 194(8):1171–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Asselin-Paturel C et al. (2001) Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol 2(12):1144–1150

    Article  CAS  PubMed  Google Scholar 

  12. Bjorck P (2001) Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. Blood 98(13):3520–3526

    Article  CAS  PubMed  Google Scholar 

  13. Kuwana M (2002) Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets. Hum Immunol 63(12):1156–1163

    Article  CAS  PubMed  Google Scholar 

  14. Moseman EA et al. (2004) Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4 + CD25+ regulatory T cells. J Immunol 173(7):4433–4442

    Article  CAS  PubMed  Google Scholar 

  15. Boonstra A et al. (2003) 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 197(1):101–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Martin P et al. (2002) Characterization of a new subpopulation of mouse CD8alpha + B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100(2):383–390

    Article  CAS  PubMed  Google Scholar 

  17. Bilsborough J et al. (2003) Mucosal CD8alpha + DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108(4):481–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ito T et al. (2007) Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J Exp Med 204(1):105–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. McKenna HJ et al. (2000) Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95(11):3489–3497

    CAS  PubMed  Google Scholar 

  20. Waskow C et al. (2008) The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol 9(6):676–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hacker C et al. (2003) Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol 4(4):380–386

    Article  CAS  PubMed  Google Scholar 

  22. Kusunoki T et al. (2003) TH2 dominance and defective development of a CD8+ dendritic cell subset in Id2-deficient mice. J Allergy Clin Immunol 111(1):136–142

    Article  CAS  PubMed  Google Scholar 

  23. Holtschke T et al. (1996) Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87(2):307–317

    Article  CAS  PubMed  Google Scholar 

  24. Schiavoni G et al. (2002) ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells. J Exp Med 196(11):1415–1425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hildner K et al. (2008) Batf3 deficiency reveals a critical role for CD8alpha + dendritic cells in cytotoxic T cell immunity. Science 322(5904):1097–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Edelson BT et al. (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha + conventional dendritic cells. J Exp Med 207(4):823–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yamazaki S et al. (2008) CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells. J Immunol 181(10):6923–6933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Belz GT et al. (2002) The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J Exp Med 196(8):1099–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Scheinecker C et al. (2002) Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 196(8):1079–1090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hawiger D et al. (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194(6):769–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bonifaz L et al. (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196(12):1627–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kretschmer K et al. (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6(12):1219–1227

    Article  CAS  PubMed  Google Scholar 

  33. Fukaya T et al. (2012) Conditional ablation of CD205+ conventional dendritic cells impacts the regulation of T-cell immunity and homeostasis in vivo. Proc Natl Acad Sci U S A 109(28):11288–11293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lewis KL et al. (2011) Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35(5):780–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Greter M et al. (2012) GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36(6):1031–1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chung Y et al. (2005) CD8alpha-11b + dendritic cells but not CD8alpha + dendritic cells mediate cross-tolerance toward intestinal antigens. Blood 106(1):201–206

    Article  CAS  PubMed  Google Scholar 

  37. Kriegel MA, Rathinam C, Flavell RA (2012) Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c + CD11b + dendritic cells. Proc Natl Acad Sci U S A 109(9):3457–3462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Park MJ et al. (2012) A distinct tolerogenic subset of splenic IDO(+)CD11b(+) dendritic cells from orally tolerized mice is responsible for induction of systemic immune tolerance and suppression of collagen-induced arthritis. Cell Immunol 278(1–2):45–54

    Article  CAS  PubMed  Google Scholar 

  39. Min SY et al. (2006) Antigen-induced, tolerogenic CD11c+,CD11b + dendritic cells are abundant in Peyer’s patches during the induction of oral tolerance to type II collagen and suppress experimental collagen-induced arthritis. Arthritis Rheum 54(3):887–898

    Article  CAS  PubMed  Google Scholar 

  40. Brocker T, Riedinger M, Karjalainen K (1997) Targeted expression of major histocompatibility complex (MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo. J Exp Med 185(3):541–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Clausen BE et al. (1998) Residual MHC class II expression on mature dendritic cells and activated B cells in RFX5-deficient mice. Immunity 8(2):143–155

    Article  CAS  PubMed  Google Scholar 

  42. Peterson P, Org T, Rebane A (2008) Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol 8(12):948–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hubert FX et al. (2011) Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118(9):2462–2472

    Article  CAS  PubMed  Google Scholar 

  44. Klein L et al. (2011) Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol 32(5):188–193

    Article  CAS  PubMed  Google Scholar 

  45. Aichinger M et al. (2013) Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J Exp Med 210(2):287–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lei Y et al. (2011) Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med 208(2):383–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Proietto AI, van Dommelen S, Wu L (2009) The impact of circulating dendritic cells on the development and differentiation of thymocytes. Immunol Cell Biol 87(1):39–45

    Article  CAS  PubMed  Google Scholar 

  48. Birnberg T et al. (2008) Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 29(6):986–997

    Article  CAS  PubMed  Google Scholar 

  49. Yogev N et al. (2012) Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 37(2):264–275

    Article  CAS  PubMed  Google Scholar 

  50. Ohnmacht C et al. (2009) Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 206(3):549–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stoll S et al. (2002) Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296(5574):1873–1876

    Article  PubMed  Google Scholar 

  52. Shakhar G et al. (2005) Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat Immunol 6(7):707–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hochweller K et al. (2010) Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc Natl Acad Sci U S A 107(13):5931–5936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Garbi N et al. (2010) Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells. Curr Opin Immunol 22(5):601–608

    Article  CAS  PubMed  Google Scholar 

  55. Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci U S A 99(1):351–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711

    Article  CAS  PubMed  Google Scholar 

  57. Dudziak D et al. (2007) Differential antigen processing by dendritic cell subsets in vivo. Science 315(5808):107–111

    Article  CAS  PubMed  Google Scholar 

  58. Probst HC et al. (2003) Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity 18(5):713–720

    Article  CAS  PubMed  Google Scholar 

  59. Probst HC et al. (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6(3):280–286

    Article  CAS  PubMed  Google Scholar 

  60. Schildknecht A et al. (2010) FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells. Proc Natl Acad Sci U S A 107(1):199–203

    Article  CAS  PubMed  Google Scholar 

  61. Hochweller K et al. (2009) Homeostasis of dendritic cells in lymphoid organs is controlled by regulation of their precursors via a feedback loop. Blood 114(20):4411–4421

    Article  CAS  PubMed  Google Scholar 

  62. Collin M et al. (2011) Human dendritic cell deficiency: the missing ID? Nat Rev Immunol 11(9):575–583

    Article  CAS  PubMed  Google Scholar 

  63. Teichmann LL et al. (2010) Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33(6):967–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yamazaki S et al. (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 198(2):235–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tarbell KV et al. (2004) CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199(11):1467–1477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Darrasse-Jeze G et al. (2009) Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med 206(9):1853–1862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Suffner J et al. (2010) Dendritic cells support homeostatic expansion of Foxp3+ regulatory T cells in Foxp3.LuciDTR mice. J Immunol 184(4):1810–1820

    Article  CAS  PubMed  Google Scholar 

  68. Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8(2):191–197

    Article  CAS  PubMed  Google Scholar 

  69. Swee LK et al. (2009) Expansion of peripheral naturally occurring T regulatory cells by fms-like tyrosine kinase 3 ligand treatment. Blood 113(25):6277–6287

    Article  CAS  PubMed  Google Scholar 

  70. Collins CB et al. (2012) Flt3 ligand expands CD103(+) dendritic cells and FoxP3(+) T regulatory cells, and attenuates Crohn’s-like murine ileitis. Gut 61(8):1154–1162

    Article  CAS  PubMed  Google Scholar 

  71. Vollstedt S et al. (2004) Treatment of neonatal mice with Flt3 ligand leads to changes in dendritic cell subpopulations associated with enhanced IL-12 and IFN-alpha production. Eur J Immunol 34(7):1849–1860

    Article  CAS  PubMed  Google Scholar 

  72. Belz GT, Nutt SL (2012) Transcriptional programming of the dendritic cell network. Nat Rev Immunol 12(2):101–113

    Article  CAS  PubMed  Google Scholar 

  73. Anandasabapathy N et al. (2014) Classical Flt3L-dependent dendritic cells control immunity to protein vaccine. J Exp Med 211(9):1875–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Salomon B et al. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12(4):431–440

    Article  CAS  PubMed  Google Scholar 

  75. Bar-On L et al. (2011) Dendritic cell-restricted CD80/86 deficiency results in peripheral regulatory T-cell reduction but is not associated with lymphocyte hyperactivation. Eur J Immunol 41(2):291–298

    Article  CAS  PubMed  Google Scholar 

  76. Coquet JM et al. (2013) Epithelial and dendritic cells in the thymic medulla promote CD4 + Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J Exp Med 210(4):715–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Soares H et al. (2007) A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo. J Exp Med 204(5):1095–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Coquet JM et al. (2013) The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity 38(1):53–65

    Article  CAS  PubMed  Google Scholar 

  79. Libregts S et al. (2011) Function of CD27 in helper T cell differentiation. Immunol Lett 136(2):177–186

    Article  CAS  PubMed  Google Scholar 

  80. Akbari O et al. (2002) Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8(9):1024–1032

    Article  CAS  PubMed  Google Scholar 

  81. Kool M et al. (2009) An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol 183(2):1074–1082

    Article  CAS  PubMed  Google Scholar 

  82. Wang C et al. (2010) Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis. J Neurosci Res 88(1):7–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Francisco LM et al. (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang L et al. (2008) Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3 + CD4+ regulatory T cells. Proc Natl Acad Sci U S A 105(27):9331–9336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fife BT et al. (2009) Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10(11):1185–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kuipers H et al. (2006) Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol 36(9):2472–2482

    Article  CAS  PubMed  Google Scholar 

  87. Moore KW et al. (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  CAS  PubMed  Google Scholar 

  88. Li MO, Flavell RA (2008) Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28(4):468–476

    Article  PubMed  CAS  Google Scholar 

  89. Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10(3):170–181

    Article  CAS  PubMed  Google Scholar 

  90. Clausen BE, Kel JM (2010) Langerhans cells: critical regulators of skin immunity? Immunol Cell Biol 88(4):351–360

    Article  CAS  PubMed  Google Scholar 

  91. Clausen BE, Girard-Madoux MJ (2013) IL-10 control of dendritic cells in the skin. Oncoimmunology 2(3):e23186

    Article  PubMed  PubMed Central  Google Scholar 

  92. Torres-Aguilar H et al. (2010) Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J Immunol 184(4):1765–1775

    Article  CAS  PubMed  Google Scholar 

  93. Steinbrink K et al. (1999) 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 93(5):1634–1642

    CAS  PubMed  Google Scholar 

  94. Muller G et al. (2002) Interleukin-10-treated dendritic cells modulate immune responses of naive and sensitized T cells in vivo. J Investig Dermatol 119(4):836–841

    Article  CAS  PubMed  Google Scholar 

  95. Perona-Wright G et al. (2007) IL-10 permits transient activation of dendritic cells to tolerize T cells and protect from central nervous system autoimmune disease. Int Immunol 19(9):1123–1134

    Article  CAS  PubMed  Google Scholar 

  96. Lan YY et al. (2006) “Alternatively activated” dendritic cells preferentially secrete IL-10, expand Foxp3 + CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig. J Immunol 177(9):5868–5877

    Article  CAS  PubMed  Google Scholar 

  97. Girard-Madoux MJ et al. (2012) IL-10 controls dendritic cell-induced T-cell reactivation in the skin to limit contact hypersensitivity. J Allergy Clin Immunol 129(1):143–150 e1-10

    Article  CAS  PubMed  Google Scholar 

  98. Girard-Madoux MJ et al. (2015) IL-10 signaling in dendritic cells attenuates anti-Leishmania major immunity without affecting protective memory responses. J Investig Dermatol 135(11):2890–2894

    Article  CAS  PubMed  Google Scholar 

  99. Zigmond E et al. (2014) Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40(5):720–733

    Article  CAS  PubMed  Google Scholar 

  100. Girard-Madoux MJ et al. (2016) IL-10 control of CD11c + myeloid cells is essential to maintain immune homeostasis in the small and large intestine. Oncotarget. doi:10.18632/oncotarget.8337

  101. Jonuleit H et al. (2000) Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192(9):1213–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Akbari O, DeKruyff RH, Umetsu DT (2001) Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2(8):725–731

    Article  CAS  PubMed  Google Scholar 

  103. Wakkach A et al. (2003) Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 18(5):605–617

    Article  CAS  PubMed  Google Scholar 

  104. Igyarto BZ et al. (2009) Langerhans cells suppress contact hypersensitivity responses via cognate CD4 interaction and langerhans cell-derived IL-10. J Immunol 183(8):5085–5093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kuhn R et al. (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274

    Article  CAS  PubMed  Google Scholar 

  106. Awasthi A et al. (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8(12):1380–1389

    Article  CAS  PubMed  Google Scholar 

  107. Sweeney CM et al. (2011) IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav Immun 25(6):1170–1181

    Article  CAS  PubMed  Google Scholar 

  108. Pot C et al. (2009) Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 183(2):797–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang H et al. (2011) IL-27 induces the differentiation of Tr1-like cells from human naive CD4+ T cells via the phosphorylation of STAT1 and STAT3. Immunol Lett 136(1):21–28

    Article  CAS  PubMed  Google Scholar 

  110. Karakhanova S et al. (2011) IL-27 renders DC immunosuppressive by induction of B7-H1. J Leukoc Biol 89(6):837–845

    Article  CAS  PubMed  Google Scholar 

  111. Mascanfroni ID et al. (2013) IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat Immunol 14(10):1054–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen W et al. (2003) Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25(3):441–454

    Article  CAS  PubMed  Google Scholar 

  114. Gorelik L, Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171–181

    Article  CAS  PubMed  Google Scholar 

  115. Zhang X et al. (2005) CD4-8- dendritic cells prime CD4+ T regulatory 1 cells to suppress antitumor immunity. J Immunol 175(5):2931–2937

    Article  CAS  PubMed  Google Scholar 

  116. Geissmann F et al. (1999) TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 162(8):4567–4575

    CAS  PubMed  Google Scholar 

  117. Ohtani T et al. (2009) TGF-beta1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation. Immunology 126(4):485–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ramalingam R et al. (2012) Dendritic cell-specific disruption of TGF-beta receptor II leads to altered regulatory T cell phenotype and spontaneous multiorgan autoimmunity. J Immunol 189(8):3878–3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mu D et al. (2002) The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol 157(3):493–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Travis MA et al. (2007) Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449(7160):361–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kel JM et al. (2010) TGF-beta is required to maintain the pool of immature Langerhans cells in the epidermis. J Immunol 185(6):3248–3255

    Article  CAS  PubMed  Google Scholar 

  122. Iwata M et al. (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21(4):527–538

    Article  CAS  PubMed  Google Scholar 

  123. Mucida D et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835):256–260

    Article  CAS  PubMed  Google Scholar 

  124. Hill JA et al. (2008) Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4 + CD44hi cells. Immunity 29(5):758–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sun CM et al. (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204(8):1775–1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Coombes JL et al. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204(8):1757–1764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Guilliams M et al. (2010) Skin-draining lymph nodes contain dermis-derived CD103(−) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells. Blood 115(10):1958–1968

    Article  CAS  PubMed  Google Scholar 

  128. Staal FJ, Luis TC, Tiemessen MM (2008) WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol 8(8):581–593

    Article  CAS  PubMed  Google Scholar 

  129. Jiang A et al. (2007) Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27(4):610–624

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Manicassamy S et al. (2010) Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329(5993):849–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Suryawanshi A et al. (2015) Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation. J Immunol 194(7):3295–3304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liang X et al. (2014) Beta-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8(+) T cells. J Leukoc Biol 95(1):179–190

    Article  PubMed  CAS  Google Scholar 

  133. Fu C et al. (2015) Beta-catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci U S A 112(9):2823–2828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cohen SB et al. (2015) Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells. J Immunol 194(1):210–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mellman I, Clausen BE (2010) Immunology. Beta-catenin balances immunity. Science 329(5993):767–769

    Article  CAS  PubMed  Google Scholar 

  136. Alves CH et al. (2015) Dendritic cell-specific deletion of beta-catenin results in fewer regulatory T-cells without exacerbating autoimmune collagen-induced arthritis. PLoS One 10(11):e0142972

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Fallarino F et al. (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761

    Article  CAS  PubMed  Google Scholar 

  138. Mezrich JD et al. (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185(6):3190–3198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nguyen NT et al. (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A 107(46):19961–19966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Quintana FJ et al. (2010) An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 107(48):20768–20773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Grohmann U et al. (2007) Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 13(5):579–586

    Article  CAS  PubMed  Google Scholar 

  143. Fallarino F et al. (2002) Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells. Int Immunol 14(1):65–68

    Article  CAS  PubMed  Google Scholar 

  144. Matteoli G et al. (2010) Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut 59(5):595–604

    Article  CAS  PubMed  Google Scholar 

  145. Grohmann U et al. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3(11):1097–1101

    Article  CAS  PubMed  Google Scholar 

  146. Fallarino F et al. (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4(12):1206–1212

    Article  CAS  PubMed  Google Scholar 

  147. Mellor AL et al. (2004) Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 16(10):1391–1401

    Article  CAS  PubMed  Google Scholar 

  148. Yan Y et al. (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185(10):5953–5961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lutz MB (2012) Therapeutic potential of semi-mature dendritic cells for tolerance induction. Front Immunol 3:123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hilkens CM, Isaacs JD, Thomson AW (2010) Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol 29(2):156–183

    Article  CAS  PubMed  Google Scholar 

  151. Brandl C et al. (2010) B7-H1-deficiency enhances the potential of tolerogenic dendritic cells by activating CD1d-restricted type II NKT cells. PLoS One 5(5):e10800

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Kleindienst P et al. (2005) Simultaneous induction of CD4 T cell tolerance and CD8 T cell immunity by semimature dendritic cells. J Immunol 174(7):3941–3947

    Article  CAS  PubMed  Google Scholar 

  153. Lim DS et al. (2009) Semi-mature DC are immunogenic and not tolerogenic when inoculated at a high dose in collagen-induced arthritis mice. Eur J Immunol 39(5):1334–1343

    Article  CAS  PubMed  Google Scholar 

  154. Menges M et al. (2002) Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity. J Exp Med 195(1):15–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Sato K et al. (2003) Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18(3):367–379

    Article  CAS  PubMed  Google Scholar 

  156. Stoop JN et al. (2010) Therapeutic effect of tolerogenic dendritic cells in established collagen-induced arthritis is associated with a reduction in Th17 responses. Arthritis Rheum 62(12):3656–3665

    Article  PubMed  Google Scholar 

  157. Verginis P, Li HS, Carayanniotis G (2005) Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4 + CD25+ T cells. J Immunol 174(11):7433–7439

    Article  CAS  PubMed  Google Scholar 

  158. Dhodapkar MV et al. (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193(2):233–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Fong L et al. (2001) Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 166(6):4254–4259

    Article  CAS  PubMed  Google Scholar 

  160. Boks MA et al. (2012) IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction—a comparative study of human clinical-applicable DC. Clin Immunol 142(3):332–342

    Article  CAS  PubMed  Google Scholar 

  161. Galluzzi L et al. (2012) Trial watch: dendritic cell-based interventions for cancer therapy. Oncoimmunology 1(7):1111–1134

    Article  PubMed  PubMed Central  Google Scholar 

  162. Kepp O et al. (2012) Anticancer activity of cardiac glycosides: at the frontier between cell-autonomous and immunological effects. Oncoimmunology 1(9):1640–1642

    Article  PubMed  PubMed Central  Google Scholar 

  163. Giannoukakis N et al. (2011) Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care 34(9):2026–2032

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Tommy Regen, Ronald Backer and Julia Ober-Blöbaum for critical reading of the manuscript. Research that is relevant for this review is and has been supported by grants from, respectively, the DFG (SFB TR128 and TR156 to AW) and the NWO (VIDI 917-76-365 to BEC) as well as by the Forschungszentrum für Immuntherapie (FZI) Mainz.

Author information

Authors and Affiliations

  1. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    Ari Waisman, Dominika Lukas, Björn E. Clausen & Nir Yogev

  2. Department of Microbiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    Dominika Lukas

  3. Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    Nir Yogev

Authors
  1. Ari Waisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dominika Lukas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Björn E. Clausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nir Yogev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ari Waisman.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

This article is a contribution to the special issue on Dendritic Cell Subsets and Immune-mediated Diseases - Guest Editor: Francisco Quintana

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waisman, A., Lukas, D., Clausen, B.E. et al. Dendritic cells as gatekeepers of tolerance. Semin Immunopathol 39, 153–163 (2017). https://doi.org/10.1007/s00281-016-0583-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-016-0583-z

Keywords

Search

Navigation