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Factors and signals that govern the migration of dendritic cells via lymphatics: recent advances

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Abstract

Dendritic cell (DC) migration from peripheral organs to lymph nodes plays a key role in initiating immune responses, whether migratory DCs bring antigen in tow to lymph nodes or position themselves to capture antigen that drains into the lymph node. CCR7 prominently controls DC migration into afferent lymphatic vessels and the positioning of DCs within the lymph node. Expression of CCR7 is not sufficient for function, as its function is positively regulated by a variety of other extracellular triggers. At least one of these triggers, synthesis and secretion of PGE2, is brought on by the activation of p38 MAP kinase. The MAP kinase pathway has been well studied in DCs and exhibits a complex regulatory role in which the activation of different MAP kinase members leads to biologically distinct outcomes that are dependent upon stage of differentiation at the time of activation as well as the duration of signaling. Almost all of our knowledge of how DCs mature and ultimately mobilize to lymph nodes comes from studies in which DC migration is probed in the context of immune activation and priming. A reasonable body of evidence has gathered to suggest that many molecular events important for DC migration in this context do not affect accumulation of DCs in lymph nodes in the steady state, but mediators that interface with the signaling adaptor DAP-12 may play key roles in the steady state. It may thus become possible to devise approaches to modulate DC mobilization in the context of inflammation without affecting the traffic of DCs during more quiescent conditions. Considering the finely tuned regulation of DC maturation, migration, and cytokine production, with the realization that these phenotypes can be mutually exclusive, manipulation of DC migration in the clinic will be a challenging, albeit feasible, task.

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References

  1. Angeli V, Faveeuw C, Roye O, et al (2001) Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection. J Exp Med 193:1135

    Google Scholar 

  2. Angeli V, Hammad H, Staels B, et al (2003) Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response. J Immunol 170:5295

    Google Scholar 

  3. Ardeshna KM, Pizzey AR, Walker SJ, et al (2002) The upregulation of CC chemokine receptor 7 and the increased migration of maturing dendritic cells to macrophage inflammatory protein 3beta and secondary lymphoid chemokine is mediated by the p38 stress-activated protein kinase pathway. Br J Haematol 119:826

    Google Scholar 

  4. Arrighi JF, Rebsamen M, Rousset F, et al (2001) A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J Immunol 166:3837

    Google Scholar 

  5. Ato M, Stager S, Engwerda CR, et al (2002) Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol 3:1185

    Google Scholar 

  6. Bakker AB, Hoek RM, Cerwenka A, et al (2000) DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13:345

    Google Scholar 

  7. Bonifaz LC, Bonnyay DP, Charalambous A, et al (2004) In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor Improves T cell vaccination. J Exp Med 199:815

    Google Scholar 

  8. Bouchon A, Hernandez-Munain C, Cella M, et al (2001) A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194:1111

    Google Scholar 

  9. Brand CU, Hunger RE, Yawalkar N, et al (1999) Characterization of human skin-derived CD1a-positive lymph cells. Arch Dermatol Res 291:65

    Google Scholar 

  10. Branger J, Blink B van den, Weijer S, et al (2002) Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol 168:4070

    Google Scholar 

  11. Cavanagh LL, Von Andrian UH (2002) Travellers in many guises: the origins and destinations of dendritic cells. Immunol Cell Biol 80:448

    Google Scholar 

  12. Chen T, Guo J, Yang M, et al (2004) Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression. Blood 103:413

    Google Scholar 

  13. Colonna M (2003) TREMs in the immune system and beyond. Nat Rev Immunol 3:445

    Google Scholar 

  14. Daws MR, Sullam PM, Niemi EC, et al (2003) Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 171:594

    Google Scholar 

  15. Daynes RA, Jones DC (2002) Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2:748

    Google Scholar 

  16. De Bono JS, Rowinsky EK (2002) Therapeutics targeting signal transduction for patients with colorectal carcinoma. Br Med Bull 64:227

    Google Scholar 

  17. Dumitru CD, Ceci JD, Tsatsanis C, et al (2000) TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103:1071

    Google Scholar 

  18. Eliopoulos AG, Dumitru CD, Wang CC, et al (2002) Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J 21:4831

    Google Scholar 

  19. Farina C, Theil D, Semlinger B, et al (2004) Distinct responses of monocytes to Toll-like receptor ligands and inflammatory cytokines. Int Immunol 16:799

    Google Scholar 

  20. Flores-Romo L (2001) In vivo maturation and migration of dendritic cells. Immunology 102:255

    Google Scholar 

  21. Förster R, Schubel A, Breitfeld D, et al (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23

    Google Scholar 

  22. Fukunaga A, Nagai H, Noguchi T, et al (2004) SRC homology 2 domain-containing protein tyrosine phosphatase substrate 1 regulates the migration of langerhans cells from the epidermis to draining lymph nodes J Immunol 172:4091

    Google Scholar 

  23. Geissmann F, Dieu-Nosjean MC, Dezutter C, et al (2002) Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin. J Exp Med 196:417

    Google Scholar 

  24. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225

    Google Scholar 

  25. Guha M, Mackman N (2001) LPS induction of gene expression in human monocytes. Cell Signal 13:85

    Google Scholar 

  26. Harizi H, Grosset C, Gualde N (2003) Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes. J Leukoc Biol 73:756

    Google Scholar 

  27. Hashimoto S, Kawai Y, Ohhashi T (1994) Effects of vasoactive substances on the pig isolated hepatic lymph vessels. J Pharmacol Exp Ther 269:482

    Google Scholar 

  28. Higashida H, Hashii M, Yokoyama S, et al (2001) Cyclic ADP-ribose as a second messenger revisited from a new aspect of signal transduction from receptors to ADP-ribosyl cyclase. Pharmacol Ther 90:283

    Google Scholar 

  29. Hofer S, Ivarsson L, Stoitzner P, et al (2003) Adenosine slows migration of dendritic cells but does not affect other aspects of dendritic cell maturation. J Invest Dermatol 121:300

    Google Scholar 

  30. Ibata-Ombetta S, Jouault T, Trinel PA, et al (2001) Role of extracellular signal-regulated protein kinase cascade in macrophage killing of Candida albicans. J Leukoc Biol 70:149

    Google Scholar 

  31. Ikomi F, Hunt J, Hanna G, et al (1996) Interstitial fluid, plasma protein, colloid, and leukocyte uptake into initial lymphatics. J Appl Physiol 81:2060

    Google Scholar 

  32. Irjala H, Alanen K, Grenman R, et al (2003) Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium. Cancer Res 63:4671

    Google Scholar 

  33. Irjala H, Elima K, Johansson EL, et al (2003) The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels. Eur J Immunol 33:815

    Google Scholar 

  34. Itano AA, McSorley SJ, Reinhardt RL, et al (2003) Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19:47

    Google Scholar 

  35. Jolles S, Christensen J, Holman M, et al (2002) Systemic treatment with anti-CD40 antibody stimulates Langerhans cell migration from the skin. Clin Exp Immunol 129:519

    Google Scholar 

  36. Jonuleit H, Kuhn U, Muller G, et al (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27:3135

    Google Scholar 

  37. Kabashima K, Sakata D, Nagamachi M, et al (2003) Prostaglandin E(2)-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med 9:744

    Google Scholar 

  38. Kamath AT, Henri S, Battye F, et al (2002) Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100:1734

    Google Scholar 

  39. Kelly D, Campbell JI, King TP, et al (2004) Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol 5:104

    Google Scholar 

  40. Kobayashi H, Miura S, Nagata H, et al (2004) In situ demonstration of dendritic cell migration from rat intestine to mesenteric lymph nodes: relationships to maturation and role of chemokines. J Leukoc Biol 75:434

    Google Scholar 

  41. Kruh GD, Belinsky MG (2003) The MRP family of drug efflux pumps. Oncogene 22:7537

    Google Scholar 

  42. Latour S, Tanaka H, Demeure C, et al (2001) Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation. J Immunol 167:2547

    Google Scholar 

  43. Lee AW, Truong T, Bickham K, et al (2002) A clinical grade cocktail of cytokines and PGE2 results in uniform maturation of human monocyte-derived dendritic cells: implications for immunotherapy. Vaccine 20 (Suppl 4):A8

  44. Lohoff M, Precht S, Sommer F, et al (1998) A multidrug-resistance protein (MRP)-like transmembrane pump is highly expressed by resting murine T helper (Th)2, but not Th1 cells, and is induced to equal expression levels in Th1 and Th2 cells after antigenic stimulation in vivo. J Clin Invest 101:703

    Google Scholar 

  45. Luft T, Jefford M, Luetjens P, et al (2002) Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets. Blood 100:1362

    Google Scholar 

  46. Luft T, Maraskovsky E, Schnurr M, et al (2004) Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells. Blood (in press)

  47. MacPherson GG, Jenkins CD, Stein MJ, et al (1995) Endotoxin-mediated dendritic cell release from the intestine. Characterization of released dendritic cells and TNF dependence. J Immunol 154:1317

    Google Scholar 

  48. MartIn-Fontecha A, Sebastiani S, Hopken UE, et al (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198:615

    Google Scholar 

  49. Mathur RK, Awasthi A, Wadhone P, et al (2004) Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat Med 10:540

    Google Scholar 

  50. Mempel TR, Henrickson SE, Von Andrian UH (2004) T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427:154

    Google Scholar 

  51. Moodycliffe AM, Shreedhar V, Ullrich SE, et al (2000) CD40-CD40 ligand interactions in vivo regulate migration of antigen-bearing dendritic cells from the skin to draining lymph nodes. J Exp Med 191:2011

    Google Scholar 

  52. Norbury CC, Malide D, Gibbs JS, et al (2002) Visualizing priming of virus-specific CD8+ T cells by infected dendritic cells in vivo. Nat Immunol 3:265

    Google Scholar 

  53. Norgauer J, Ibig Y, Gmeiner D, et al (2003) Prostaglandin E2 synthesis in human monocyte-derived dendritic cells. Int J Mol Med 12:83

    Google Scholar 

  54. Ortolan E, Vacca P, Capobianco A, et al (2002) CD157, the Janus of CD38 but with a unique personality. Cell Biochem Funct 20:309

    Google Scholar 

  55. Ouaaz F, Arron J, Zheng Y, et al (2002) Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 16:257

    Google Scholar 

  56. Paloneva J, Kestila M, Wu J, et al (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25:357

    Google Scholar 

  57. Paloneva J, Manninen T, Christman G, et al (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656

    Google Scholar 

  58. Palucka KA, Taquet N, Sanchez-Chapuis F, et al (1999) Lipopolysaccharide can block the potential of monocytes to differentiate into dendritic cells. J Leukoc Biol 65:232

    Google Scholar 

  59. Partida-Sanchez S, Cockayne DA, Monard S, et al (2001) Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med 7:1209

    Google Scholar 

  60. Partida-Sanchez S, Goodrich S, Kusser K, et al (2004) Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact on the development of humoral immunity. Immunity 20:279

    Google Scholar 

  61. Penna G, Vulcano M, Sozzani S, et al (2002) Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Hum Immunol 63:1164

    Google Scholar 

  62. Pugh CW, MacPherson GG, Steer HW (1983) Characterization of nonlymphoid cells derived from rat peripheral lymph. J Exp Med 157:1758

    Google Scholar 

  63. Puig-Kroger A, Relloso M, Fernandez-Capetillo O, et al (2001) Extracellular signal-regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells. Blood 98:2175

    Google Scholar 

  64. Randolph GJ (2001) Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators. Semin Immunol 13:267

    Google Scholar 

  65. Randolph GJ (2002) Is maturation required for langerhans cell migration? J Exp Med 196:413

    Google Scholar 

  66. Randolph GJ, Inaba K, Robbiani DF, et al (1999) Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11:753

    Google Scholar 

  67. Reid G, Wielinga P, Zelcer N, et al (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol 63:1094

    Google Scholar 

  68. Rius M, Nies AT, Hummel-Eisenbeiss J, et al (2003) Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology 38:374

    Google Scholar 

  69. Robbiani DF, Finch RA, Jager D, et al (2000) The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103:757

    Google Scholar 

  70. Romani N, Ratzinger G, Pfaller K, et al (2001) Migration of dendritic cells into lymphatics-the Langerhans cell example: routes, regulation, and relevance. Int Rev Cytol 207:237

    Google Scholar 

  71. Rotta G, Edwards EW, Sangaletti S, et al (2003) Lipopolysaccharide or whole bacteria block the conversion of inflammatory monocytes into dendritic cells in vivo. J Exp Med 198:1253

    Google Scholar 

  72. Saeki H, Moore AM, Brown MJ, et al (1999) Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 162:2472

    Google Scholar 

  73. Sato K, Nagayama H, Tadokoro K, et al (1999) Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38mapk are involved in IL-10-mediated selective repression of TNF-alpha-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells. J Immunol 162:3865

    Google Scholar 

  74. Scandella E, Men Y, Gillessen S, et al (2002) Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood 100:1354

    Google Scholar 

  75. Scandella E, Men Y, Legler DF, et al (2004) CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2. Blood 103:1595

    Google Scholar 

  76. Sjostrom M, Johansson AS, Schroder O, et al (2003) Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 23:e37

    Google Scholar 

  77. Sozzani S, Allavena P, Vecchi A, et al (2000) Chemokines and dendritic cell traffic. J Clin Immunol 20:151

    Google Scholar 

  78. Takashima A, Mummert M, Kitajima T, et al (2000) New technologies to prevent and treat contact hypersensitivity responses. Ann N Y Acad Sci 919:205

    Google Scholar 

  79. Thomas PG, Carter MR, Atochina O, et al (2003) Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-dependent mechanism. J Immunol 171:5837

    Google Scholar 

  80. Verbovetski I, Bychkov H, Trahtemberg U, et al (2002) Opsonization of apoptotic cells by autologous iC3b facilitates clearance by immature dendritic cells, down-regulates DR and CD86, and up-regulates CC chemokine receptor 7. J Exp Med 196:1553

    Google Scholar 

  81. Waterfield MR, Zhang M, Norman LP, et al (2003) NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol Cell 11:685

    Google Scholar 

  82. Weiss JM, Sleeman J, Renkl AC, et al (1997) An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function. J Cell Biol 137:1137

    Google Scholar 

  83. Weiss JM, Renkl AC, Maier CS, et al (2001) Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and dendritic cell migration to lymph nodes. J Exp Med 194:1219

    Google Scholar 

  84. Xie J, Qian J, Wang S, et al (2003) Novel and detrimental effects of lipopolysaccharide on in vitro generation of immature dendritic cells: involvement of mitogen-activated protein kinase p38. J Immunol 171:4792

    Google Scholar 

  85. Xu H, Guan H, Zu G, et al (2001) The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur J Immunol 31:3085

    Google Scholar 

  86. Yu Q, Kovacs C, Yue FY, et al (2004) The role of the p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide-3-OH kinase signal transduction pathways in CD40 ligand-induced dendritic cell activation and expansion of virus-specific CD8+ T cell memory responses. J Immunol 172:6047

    Google Scholar 

  87. Zoltzer H (2003) Initial lymphatics—morphology and function of the endothelial cells. Lymphology 36:7

    Google Scholar 

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  1. Department of Gene and Cell Medicine, Mt. Sinai School of Medicine, 1425 Madison Avenue, New York, NY, 10029, USA

    Gwendalyn J. Randolph, Guzman Sanchez-Schmitz & Veronique Angeli

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  1. Gwendalyn J. Randolph
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Randolph, G.J., Sanchez-Schmitz, G. & Angeli, V. Factors and signals that govern the migration of dendritic cells via lymphatics: recent advances. Springer Semin Immun 26, 273–287 (2005). https://doi.org/10.1007/s00281-004-0168-0

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