Journal of Molecular Medicine

, Volume 88, Issue 9, pp 873–880 | Cite as

Regulation of antigen uptake, migration, and lifespan of dendritic cell by Toll-like receptors



Dendritic cells (DCs) sense the presence of pathogens through germline-encoded pattern recognition receptors (PRRs), which recognize molecular patterns expressed by various microorganisms and endogenous stimuli. Toll-like receptors (TLRs) are the best characterized PRRs. TLR activation has a profound effect on a number of DC activities, including endocytosis, cytoskeleton rearrangement, migration, antigen processing and presentation, survival, and death. The goal of TLR-induced DC reprogramming is to promote the appropriate activation and differentiation of lymphocytes bearing clonally distributed antigen-specific receptors. In this review, we will focus on the functional consequences of TLR engagement for conventional DCs.


Dendritic cells Toll-like receptors CD14 Innate immunity Apoptosis 


  1. 1.
    Steinman RM, Cohn ZA (1973) Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 137:1142–1162CrossRefPubMedGoogle Scholar
  2. 2.
    Granucci F, Vizzardelli C, Pavelka N, Feau S, Persico M, Virzi E et al (2001) Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol 2:882–888CrossRefPubMedGoogle Scholar
  3. 3.
    Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3:984–993CrossRefPubMedGoogle Scholar
  4. 4.
    Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17–58CrossRefPubMedGoogle Scholar
  5. 5.
    van Vliet SJ, den Dunnen J, Gringhuis SI, Geijtenbeek TB, van Kooyk Y (2007) Innate signaling and regulation of dendritic cell immunity. Curr Opin Immunol 19:435–440CrossRefPubMedGoogle Scholar
  6. 6.
    Joffre O, Nolte MA, Sporri R, Reis e Sousa C (2009) Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol Rev 227:234–247CrossRefPubMedGoogle Scholar
  7. 7.
    Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7:19–30CrossRefPubMedGoogle Scholar
  8. 8.
    Ardavin C (2003) Origin, precursors and differentiation of mouse dendritic cells. Nat Rev Immunol 3:582–590CrossRefPubMedGoogle Scholar
  9. 9.
    Ardavin C, Martinez del Hoyo G, Martin P, Anjuere F, Arias CF, Marin AR et al (2001) Origin and differentiation of dendritic cells. Trends Immunol 22:691–700CrossRefPubMedGoogle Scholar
  10. 10.
    Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nat Rev Immunol 2:151–161CrossRefPubMedGoogle Scholar
  11. 11.
    Henri S, Siret C, Machy P, Kissenpfennig A, Malissen B, Leserman L (2007) Mature DC from skin and skin-draining LN retain the ability to acquire and efficiently present targeted antigen. Eur J Immunol 37:1184–1193CrossRefPubMedGoogle Scholar
  12. 12.
    Miyake K (2007) Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19:3–10CrossRefPubMedGoogle Scholar
  13. 13.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216CrossRefPubMedGoogle Scholar
  14. 14.
    West AP, Koblansky AA, Ghosh S (2006) Recognition and signaling by toll-like receptors. Annu Rev Cell Dev Biol 22:409–437CrossRefPubMedGoogle Scholar
  15. 15.
    Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32CrossRefPubMedGoogle Scholar
  16. 16.
    Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F et al (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869CrossRefPubMedGoogle Scholar
  17. 17.
    Muzio M, Bosisio D, Polentarutti N, D'Amico G, Stoppacciaro A, Mancinelli R et al (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164:5998–6004PubMedGoogle Scholar
  18. 18.
    Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R et al (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 31:3026–3037CrossRefPubMedGoogle Scholar
  19. 19.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T et al (2002) Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537PubMedGoogle Scholar
  20. 20.
    Schattenberg D, Schott M, Reindl G, Krueger T, Tschoepe D, Feldkamp J et al (2000) Response of human monocyte-derived dendritic cells to immunostimulatory DNA. Eur J Immunol 30:2824–2831CrossRefPubMedGoogle Scholar
  21. 21.
    Edwards AD, Diebold SS, Slack EM, Tomizawa H, Hemmi H, Kaisho T et al (2003) Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha + DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol 33:827–833CrossRefPubMedGoogle Scholar
  22. 22.
    Kaisho T, Akira S (2006) Toll-like receptor function and signaling. J Allergy Clin Immunol 117:979–987, quiz 988CrossRefPubMedGoogle Scholar
  23. 23.
    Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9CrossRefPubMedGoogle Scholar
  24. 24.
    Yang K, Puel A, Zhang S, Eidenschenk C, Ku CL, Casrouge A et al (2005) Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 23:465–478CrossRefPubMedGoogle Scholar
  25. 25.
    Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S et al (2006) Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol 24:353–389CrossRefPubMedGoogle Scholar
  26. 26.
    Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nat Immunol 7:131–137CrossRefPubMedGoogle Scholar
  27. 27.
    Stetson DB, Medzhitov R (2006) Type I interferons in host defense. Immunity 25:373–381CrossRefPubMedGoogle Scholar
  28. 28.
    Barbalat R, Lau L, Locksley RM, Barton GM (2009) Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat Immunol 10:1200–1207CrossRefPubMedGoogle Scholar
  29. 29.
    Dietrich N, Lienenklaus S, Weiss S, Gekara NO (2010) Murine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments. PLoS One 5:e10250CrossRefPubMedGoogle Scholar
  30. 30.
    Barton GM, Kagan JC (2009) A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9:535–542CrossRefPubMedGoogle Scholar
  31. 31.
    Granucci F, Vizzardelli C, Virzi E, Rescigno M, Ricciardi-Castagnoli P (2001) Transcriptional reprogramming of dendritic cells by differentiation stimuli. Eur J Immunol 31:2539–2546CrossRefPubMedGoogle Scholar
  32. 32.
    West MA, Wallin RP, Matthews SP, Svensson HG, Zaru R, Ljunggren HG et al (2004) Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling. Science 305:1153–1157CrossRefPubMedGoogle Scholar
  33. 33.
    Granucci F, Ferrero E, Foti M, Aggujaro D, Vettoretto K, Ricciardi-Castagnoli P (1999) Early events in dendritic cell maturation induced by LPS. Microbes Infect 1:1079–1084CrossRefPubMedGoogle Scholar
  34. 34.
    Svensson HG, West MA, Mollahan P, Prescott AR, Zaru R, Watts C (2008) A role for ARF6 in dendritic cell podosome formation and migration. Eur J Immunol 38:818–828CrossRefPubMedGoogle Scholar
  35. 35.
    Granucci F, Petralia F, Urbano M, Citterio S, Di Tota F, Santambrogio L et al (2003) The scavenger receptor MARCO mediates cytoskeleton rearrangements in dendritic cells and microglia. Blood 102:2940–2947CrossRefPubMedGoogle Scholar
  36. 36.
    Ross R, Ross XL, Schwing J, Langin T, Reske-Kunz AB (1998) The actin-bundling protein fascin is involved in the formation of dendritic processes in maturing epidermal Langerhans cells. J Immunol 160:3776–3782PubMedGoogle Scholar
  37. 37.
    Bros M, Ross XL, Pautz A, Reske-Kunz AB, Ross R (2003) The human fascin gene promoter is highly active in mature dendritic cells due to a stage-specific enhancer. J Immunol 171:1825–1834PubMedGoogle Scholar
  38. 38.
    Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J et al (2004) CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21:279–288CrossRefPubMedGoogle Scholar
  39. 39.
    Randolph GJ, Ochando J, Partida-Sanchez S (2008) Migration of dendritic cell subsets and their precursors. Annu Rev Immunol 26:293–316CrossRefPubMedGoogle Scholar
  40. 40.
    Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT et al (1999) Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 189:451–460CrossRefPubMedGoogle Scholar
  41. 41.
    Ato M, Stager S, Engwerda CR, Kaye PM (2002) Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol 3:1185–1191CrossRefPubMedGoogle Scholar
  42. 42.
    Faure-Andre G, Vargas P, Yuseff MI, Heuze M, Diaz J, Lankar D et al (2008) Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 322:1705–1710CrossRefPubMedGoogle Scholar
  43. 43.
    Savina A, Amigorena S (2007) Phagocytosis and antigen presentation in dendritic cells. Immunol Rev 219:143–156CrossRefPubMedGoogle Scholar
  44. 44.
    Lennon-Dumenil AM, Bakker AH, Maehr R, Fiebiger E, Overkleeft HS, Rosemblatt M et al (2002) Analysis of protease activity in live antigen-presenting cells shows regulation of the phagosomal proteolytic contents during dendritic cell activation. J Exp Med 196:529–540CrossRefPubMedGoogle Scholar
  45. 45.
    Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES (2005) Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307:1630–1634CrossRefPubMedGoogle Scholar
  46. 46.
    Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A (1997) Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388:782–787CrossRefPubMedGoogle Scholar
  47. 47.
    Pierre P, Turley SJ, Meltzer J, Mirza A, Steinman R, Mellman I (1997) Localization and intracellular transport of MHC class II molecules in bone marrow-derived dendritic cells. Adv Exp Med Biol 417:179–182PubMedGoogle Scholar
  48. 48.
    Rescigno M, Citterio S, Thery C, Rittig M, Medaglini D, Pozzi G et al (1998) Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells. Proc Natl Acad Sci U S A 95:5229–5234CrossRefPubMedGoogle Scholar
  49. 49.
    Ebstein F, Lange N, Urban S, Seifert U, Kruger E, Kloetzel PM (2009) Maturation of human dendritic cells is accompanied by functional remodelling of the ubiquitin-proteasome system. Int J Biochem Cell Biol 41:1205–1215CrossRefPubMedGoogle Scholar
  50. 50.
    Ossendorp F, Fu N, Camps M, Granucci F, Gobin SJ, van den Elsen PJ et al (2005) Differential expression regulation of the alpha and beta subunits of the PA28 proteasome activator in mature dendritic cells. J Immunol 174:7815–7822PubMedGoogle Scholar
  51. 51.
    Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I (2003) Activation of lysosomal function during dendritic cell maturation. Science 299:1400–1403CrossRefPubMedGoogle Scholar
  52. 52.
    Blander JM, Medzhitov R (2006) Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440:808–812CrossRefPubMedGoogle Scholar
  53. 53.
    Lutz MB, Rovere P, Kleijmeer MJ, Rescigno M, Assmann CU, Oorschot VM et al (1997) Intracellular routes and selective retention of antigens in mildly acidic cathepsin D/lysosome-associated membrane protein-1/MHC class II-positive vesicles in immature dendritic cells. J Immunol 159:3707–3716PubMedGoogle Scholar
  54. 54.
    Rock KL, Gamble S, Rothstein L (1990) Presentation of exogenous antigen with class I major histocompatibility complex molecules. Science 249:918–921CrossRefPubMedGoogle Scholar
  55. 55.
    Schlosser E, Mueller M, Fischer S, Basta S, Busch DH, Gander B et al (2008) TLR ligands and antigen need to be coencapsulated into the same biodegradable microsphere for the generation of potent cytotoxic T lymphocyte responses. Vaccine 26:1626–1637CrossRefPubMedGoogle Scholar
  56. 56.
    Park Y, Lee SW, Sung YC (2002) Cutting Edge: CpG DNA inhibits dendritic cell apoptosis by up-regulating cellular inhibitor of apoptosis proteins through the phosphatidylinositide-3'-OH kinase pathway. J Immunol 168:5–8PubMedGoogle Scholar
  57. 57.
    Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P (1998) Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 188:2175–2180CrossRefPubMedGoogle Scholar
  58. 58.
    Matsue H, Takashima A (1999) Apoptosis in dendritic cell biology. J Dermatol Sci 20:159–171CrossRefPubMedGoogle Scholar
  59. 59.
    Kobayashi M, Saitoh S, Tanimura N, Takahashi K, Kawasaki K, Nishijima M et al (2006) Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol 176:6211–6218PubMedGoogle Scholar
  60. 60.
    Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi AE et al (2009) CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature 460:264–268CrossRefPubMedGoogle Scholar
  61. 61.
    Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M et al (1999) Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98:47–58CrossRefPubMedGoogle Scholar
  62. 62.
    Chen M, Wang YH, Wang Y, Huang L, Sandoval H, Liu YJ et al (2006) Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311:1160–1164CrossRefPubMedGoogle Scholar
  63. 63.
    Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA et al (2007) Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26:629–641CrossRefPubMedGoogle Scholar
  64. 64.
    Fujikado N, Saijo S, Yonezawa T, Shimamori K, Ishii A, Sugai S et al (2008) Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat Med 14:176–180CrossRefPubMedGoogle Scholar
  65. 65.
    Lorentzen JC, Flornes L, Eklow C, Backdahl L, Ribbhammar U, Guo JP et al (2007) Association of arthritis with a gene complex encoding C-type lectin-like receptors. Arthritis Rheum 56:2620–2632CrossRefPubMedGoogle Scholar
  66. 66.
    Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp Quant Biol 54(Pt 1):1–13PubMedGoogle Scholar
  67. 67.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Biotechnology and BioscienceUniversity of Milano-BicoccaMilanItaly

Personalised recommendations