The lymphatic vasculature is not considered a formal part of the immune system, but it is critical to immunity. One of its major roles is in the coordination of the trafficking of antigen and immune cells. However, other roles in immunity are emerging. Lymphatic endothelial cells, for example, directly present antigen or express factors that greatly influence the local environment. We cover these topics herein and discuss how other properties of the lymphatic vasculature, such as mechanisms of lymphatic contraction (which immunologists traditionally do not take into account), are nonetheless integral in the immune system. Much is yet unknown, and this nascent subject is ripe for exploration. We argue that to consider the impact of lymphatic biology in any given immunological interaction is a key step toward integrating immunology with organ physiology and ultimately many complex pathologies.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. 1.  2012. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483:227–31 [Google Scholar]
  2. Steinert EM, Schenkel JM, Fraser KA, Beura LK, Manlove LS. 2.  et al. 2015. Quantifying Memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161:737–49 [Google Scholar]
  3. Masopust D, Vezys V, Marzo AL, Lefrancois L. 3.  2001. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413–17 [Google Scholar]
  4. Reinhardt RL, Khoruts A, Merica R, Zell T, Jenkins MK. 4.  2001. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410:101–5 [Google Scholar]
  5. Roozendaal R, Mebius RE. 5.  2011. Stromal cell–immune cell interactions. Annu. Rev. Immunol. 29:23–43 [Google Scholar]
  6. Girard JP, Moussion C, Forster R. 6.  2012. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12:762–73 [Google Scholar]
  7. Bronte V, Pittet MJ. 7.  2013. The spleen in local and systemic regulation of immunity. Immunity 39:806–18 [Google Scholar]
  8. Randolph GJ, Miller NE. 8.  2014. Lymphatic transport of high-density lipoproteins and chylomicrons. J. Clin. Investig. 124:929–35 [Google Scholar]
  9. Escolano A, Martinez-Martinez S, Alfranca A, Urso K, Izquierdo HM. 9.  et al. 2014. Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p38. EMBO J 33:1117–33 [Google Scholar]
  10. Michel CC, Phillips ME. 10.  1987. Steady-state fluid filtration at different capillary pressures in perfused frog mesenteric capillaries. J. Physiol. 388:421–35 [Google Scholar]
  11. Levick JR, Michel CC. 11.  2010. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87:198–210 [Google Scholar]
  12. Michel CC, Nanjee MN, Olszewski WL, Miller NE. 12.  2015. LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans. J. Lipid Res. 56:122–28 [Google Scholar]
  13. Stan RV, Tse D, Deharvengt SJ, Smits NC, Xu Y. 13.  et al. 2012. The diaphragms of fenestrated endothelia: gatekeepers of vascular permeability and blood composition. Dev. Cell 23:1203–18 [Google Scholar]
  14. Mehta D, Malik AB. 14.  2006. Signaling mechanisms regulating endothelial permeability. Physiol. Rev. 86:279–367 [Google Scholar]
  15. Iijima N, Iwasaki A. 15.  2016. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature 533:552–56 [Google Scholar]
  16. Wiig H, Swartz MA. 16.  2012. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol. Rev. 92:1005–60 [Google Scholar]
  17. Miller NE, Michel CC, Nanjee MN, Olszewski WL, Miller IP. 17.  et al. 2011. Secretion of adipokines by human adipose tissue in vivo: partitioning between capillary and lymphatic transport. Am. J. Physiol. Endocrinol. Metab. 301:E659–67 [Google Scholar]
  18. Negrini D, Moriondo A. 18.  2011. Lymphatic anatomy and biomechanics. J. Physiol. 589:2927–34 [Google Scholar]
  19. Chary SR, Jain RK. 19.  1989. Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching. PNAS 86:5385–89 [Google Scholar]
  20. Boardman KC, Swartz MA. 20.  2003. Interstitial flow as a guide for lymphangiogenesis. Circ. Res. 92:801–8 [Google Scholar]
  21. Randolph GJ, Angeli V, Swartz MA. 21.  2005. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5:617–28 [Google Scholar]
  22. Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. 22.  2007. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11:526–38 [Google Scholar]
  23. Kolka CM, Castro AV, Kirkman EL, Bergman RN. 23.  2015. Modest hyperglycemia prevents interstitial dispersion of insulin in skeletal muscle. Metabolism 64:330–37 [Google Scholar]
  24. Basu A, Dube S, Veettil S, Slama M, Kudva YC. 24.  et al. 2015. Time lag of glucose from intravascular to interstitial compartment in type 1 diabetes. J. Diabetes Sci. Technol. 9:63–68 [Google Scholar]
  25. Rossetti P, Bondia J, Vehi J, Fanelli CG. 25.  2010. Estimating plasma glucose from interstitial glucose: the issue of calibration algorithms in commercial continuous glucose monitoring devices. Sensors 10:10936–52 [Google Scholar]
  26. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T. 26.  et al. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–41 [Google Scholar]
  27. Swartz MA, Lund AW. 27.  2012. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12:210–19 [Google Scholar]
  28. Hagendoorn J, Padera TP, Kashiwagi S, Isaka N, Noda F. 28.  et al. 2004. Endothelial nitric oxide synthase regulates microlymphatic flow via collecting lymphatics. Circ. Res. 95:204–9 [Google Scholar]
  29. Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS. 29.  et al. 2013. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab 17:671–84 [Google Scholar]
  30. Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E. 30.  et al. 2007. Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med. 204:2349–62 [Google Scholar]
  31. Yao LC, Baluk P, Srinivasan RS, Oliver G, McDonald DM. 31.  2012. Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Am. J. Pathol. 180:2561–75 [Google Scholar]
  32. Clement CC, Santambrogio L. 32.  2013. The lymph self-antigen repertoire. Front. Immunol. 4:424 [Google Scholar]
  33. Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R. 33.  et al. 2008. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55 [Google Scholar]
  34. Lammermann T, Sixt M. 34.  2009. Mechanical modes of ‘amoeboid’ cell migration. Curr. Opin. Cell Biol. 21:636–44 [Google Scholar]
  35. Pflicke H, Sixt M. 35.  2009. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J. Exp. Med. 206:2925–35 [Google Scholar]
  36. Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun YM. 36.  et al. 2013. Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin αV. Nat. Immunol. 14:949–58 [Google Scholar]
  37. Ma J, Wang JH, Guo YJ, Sy MS, Bigby M. 37.  1994. In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Cell Immunol 158:389–99 [Google Scholar]
  38. Xu H, Guan H, Zu G, Bullard D, Hanson J. 38.  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. 31:3085–93 [Google Scholar]
  39. Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG. 39.  2006. An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J. Exp. Med. 203:2763–77 [Google Scholar]
  40. Vassileva G, Soto H, Zlotnik A, Nakano H, Kakiuchi T. 40.  et al. 1999. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190:1183–88 [Google Scholar]
  41. Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I. 41.  et al. 1999. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33 [Google Scholar]
  42. Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z. 42.  et al. 2004. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21:279–88 [Google Scholar]
  43. Randolph GJ, Bala S, Rahier JF, Johnson MW, Wang PL. 43.  et al. 2016. Lymphoid aggregates remodel lymphatic collecting vessels that serve mesenteric lymph nodes in Crohn disease. Am. J. Pathol. 186:123066–73 [Google Scholar]
  44. Debes GF, Arnold CN, Young AJ, Krautwald S, Lipp M. 44.  et al. 2005. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6:889–94 [Google Scholar]
  45. Vander Lugt B, Tubo NJ, Nizza ST, Boes M, Malissen B. 45.  et al. 2013. CCR7 plays no appreciable role in trafficking of central memory CD4 T cells to lymph nodes. J. Immunol. 191:3119–27 [Google Scholar]
  46. Weber M, Hauschild R, Schwarz J, Moussion C, de Vries I. 46.  et al. 2013. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339:328–32 [Google Scholar]
  47. Platt AM, Rutkowski JM, Martel C, Kuan EL, Ivanov S. 47.  et al. 2013. Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia. J. Immunol. 190:4608–20 [Google Scholar]
  48. Tomei AA, Siegert S, Britschgi MR, Luther SA, Swartz MA. 48.  2009. Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. J. Immunol. 183:4273–83 [Google Scholar]
  49. Nibbs RJ, Kriehuber E, Ponath PD, Parent D, Qin S. 49.  et al. 2001. The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. Am. J. Pathol. 158:867–77 [Google Scholar]
  50. Locati M, Torre YM, Galliera E, Bonecchi R, Bodduluri H. 50.  et al. 2005. Silent chemoattractant receptors: D6 as a decoy and scavenger receptor for inflammatory CC chemokines. Cytokine Growth Factor Rev 16:679–86 [Google Scholar]
  51. Weber M, Blair E, Simpson CV, O'Hara M, Blackburn PE. 51.  et al. 2004. The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Mol. Biol. Cell 15:2492–508 [Google Scholar]
  52. Martinez de la Torre Y, Locati M, Buracchi C, Dupor J, Cook DN. 52.  et al. 2005. Increased inflammation in mice deficient for the chemokine decoy receptor D6. Eur. J. Immunol. 35:1342–46 [Google Scholar]
  53. Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R. 53.  et al. 2010. The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6. Gut 59:197–206 [Google Scholar]
  54. Lee KM, McKimmie CS, Gilchrist DS, Pallas KJ, Nibbs RJ. 54.  et al. 2011. D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood 118:6220–29 [Google Scholar]
  55. Singh MD, King V, Baldwin H, Burden D, Thorrat A. 55.  et al. 2012. Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis. Am. J. Pathol. 181:1158–64 [Google Scholar]
  56. Martinez de la Torre Y, Buracchi C, Borroni EM, Dupor J, Bonecchi R. 56.  et al. 2007. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. PNAS 104:2319–24 [Google Scholar]
  57. Prevo R, Banerji S, Ferguson DJ, Clasper S, Jackson DG. 57.  2001. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J. Biol. Chem. 276:19420–30 [Google Scholar]
  58. Jackson DG. 58.  2009. Immunological functions of hyaluronan and its receptors in the lymphatics. Immunol. Rev. 230:216–31 [Google Scholar]
  59. Muto J, Morioka Y, Yamasaki K, Kim M, Garcia A. 59.  et al. 2014. Hyaluronan digestion controls DC migration from the skin. J. Clin. Investig. 124:1309–19 [Google Scholar]
  60. Jiang D, Liang J, Noble PW. 60.  2007. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23:435–61 [Google Scholar]
  61. Todd JL, Wang X, Sugimoto S, Kennedy VE, Zhang HL. 61.  et al. 2014. Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. Am. J. Respir. Crit. Care Med. 189:556–66 [Google Scholar]
  62. Kerjaschki D. 62.  2006. Lymphatic neoangiogenesis in renal transplants: a driving force of chronic rejection?. J. Nephrol. 19:403–6 [Google Scholar]
  63. Cui Y, Liu K, Monzon-Medina ME, Padera RF, Wang H. 63.  et al. 2015. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection. J. Clin. Investig. 125:4255–68 [Google Scholar]
  64. Gale NW, Prevo R, Espinosa J, Ferguson DJ, Dominguez MG. 64.  et al. 2007. Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol. Cell Biol. 27:595–604 [Google Scholar]
  65. Lynskey NN, Banerji S, Johnson LA, Holder KA, Reglinski M. 65.  et al. 2015. Rapid lymphatic dissemination of encapsulated group A streptococci via lymphatic vessel endothelial receptor-1 interaction. PLOS Pathog 11:e1005137 [Google Scholar]
  66. Lawrance W, Banerji S, Day AJ, Bhattacharjee S, Jackson DG. 66.  2016. Binding of hyaluronan to the native lymphatic vessel endothelial receptor LYVE-1 is critically dependent on receptor clustering and hyaluronan organization. J. Biol. Chem. 291:8014–30 [Google Scholar]
  67. Mummert ME, Mummert D, Edelbaum D, Hui F, Matsue H, Takashima A. 67.  2002. Synthesis and surface expression of hyaluronan by dendritic cells and its potential role in antigen presentation. J. Immunol. 169:4322–31 [Google Scholar]
  68. Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J. 68.  et al. 2006. Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J. Pathol. 209:67–77 [Google Scholar]
  69. Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H. 69.  et al. 2007. Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ. Res. 100:e47–57 [Google Scholar]
  70. Pinto AR, Paolicelli R, Salimova E, Gospocic J, Slonimsky E. 70.  et al. 2012. An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLOS ONE 7:e36814 [Google Scholar]
  71. Gautier EL, Ivanov S, Williams JW, Huang SC, Marcelin G. 71.  et al. 2014. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med. 211:1525–31 [Google Scholar]
  72. Wick N, Haluza D, Gurnhofer E, Raab I, Kasimir MT. 72.  et al. 2008. Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am. J. Pathol. 173:1202–9 [Google Scholar]
  73. Kuan EL, Ivanov S, Bridenbaugh EA, Victora G, Wang W. 73.  et al. 2015. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J. Immunol. 194:5200–10 [Google Scholar]
  74. Schmid-Schonbein GW. 74.  1990. Microlymphatics and lymph flow. Physiol. Rev. 70:987–1028 [Google Scholar]
  75. Scallan JP, Wolpers JH, Muthuchamy M, Zawieja DC, Gashev AA, Davis MJ. 75.  2012. Independent and interactive effects of preload and afterload on the pump function of the isolated lymphangion. Am. J. Physiol. Heart Circ. Physiol. 303:H809–24 [Google Scholar]
  76. Davis MJ, Scallan JP, Wolpers JH, Muthuchamy M, Gashev AA, Zawieja DC. 76.  2012. Intrinsic increase in lymphangion muscle contractility in response to elevated afterload. Am. J. Physiol. Heart Circ. Physiol. 303:H795–808 [Google Scholar]
  77. Mathias R, von der Weid PY. 77.  2013. Involvement of the NO-cGMP-K(ATP) channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis. Am. J. Physiol. Gastrointest. Liver Physiol. 304:G623–34 [Google Scholar]
  78. Scallan JP, Zawieja SD, Castorena-Gonzalez JA, Davis MJ. 78.  2016. Lymphatic pumping: mechanics, mechanisms and malfunction. J. Physiol. 594:5749–68 [Google Scholar]
  79. Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S. 79.  et al. 2007. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 21:2422–32 [Google Scholar]
  80. Ivanov S, Scallan JP, Kim KW, Werth K, Johnson MW. 80.  et al. 2016. CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J. Clin. Investig. 126:1581–91 [Google Scholar]
  81. Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T. 81.  et al. 2004. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat. Med. 10:974–81 [Google Scholar]
  82. Mellor RH, Brice G, Stanton AW, French J, Smith A. 82.  et al. 2007. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation 115:1912–20 [Google Scholar]
  83. Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK. 83.  et al. 2015. GATA2 is required for lymphatic vessel valve development and maintenance. J. Clin. Investig. 125:2979–94 [Google Scholar]
  84. Danussi C, Del Bel Belluz L, Pivetta E, Modica TM, Muro A. 84.  et al. 2013. EMILIN1/α9β1 integrin interaction is crucial in lymphatic valve formation and maintenance. Mol. Cell Biol. 33:4381–94 [Google Scholar]
  85. Davis MJ, Rahbar E, Gashev AA, Zawieja DC, JE Moore Jr. 85.  2011. Determinants of valve gating in collecting lymphatic vessels from rat mesentery. Am. J. Physiol. Heart Circ. Physiol. 301:H48–60 [Google Scholar]
  86. Scallan JP, Wolpers JH, Davis MJ. 86.  2013. Constriction of isolated collecting lymphatic vessels in response to acute increases in downstream pressure. J. Physiol. 591:443–59 [Google Scholar]
  87. Nizamutdinova IT, Maejima D, Nagai T, Bridenbaugh E, Thangaswamy S. 87.  et al. 2014. Involvement of histamine in endothelium-dependent relaxation of mesenteric lymphatic vessels. Microcirculation 21:640–48 [Google Scholar]
  88. Kurtz KH, Moor AN, Souza-Smith FM, Breslin JW. 88.  2014. Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics. Microcirculation 21:593–605 [Google Scholar]
  89. Gashev AA, Davis MJ, Zawieja DC. 89.  2002. Inhibition of the active lymph pump by flow in rat mesenteric lymphatics and thoracic duct. J. Physiol. 540:1023–37 [Google Scholar]
  90. Liao S, Cheng G, Conner DA, Huang Y, Kucherlapati RS. 90.  et al. 2011. Impaired lymphatic contraction associated with immunosuppression. PNAS 108:18784–89 [Google Scholar]
  91. Scallan JP, Davis MJ. 91.  2013. Genetic removal of basal nitric oxide enhances contractile activity in isolated murine collecting lymphatic vessels. J. Physiol. 591:2139–56 [Google Scholar]
  92. Bouta EM, Wood RW, Brown EB, Rahimi H, Ritchlin CT, Schwarz EM. 92.  2014. In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice. J. Physiol. 592:1213–23 [Google Scholar]
  93. Brown MN, Fintushel SR, Lee MH, Jennrich S, Geherin SA. 93.  et al. 2010. Chemoattractant receptors and lymphocyte egress from extralymphoid tissue: changing requirements during the course of inflammation. J. Immunol. 185:4873–82 [Google Scholar]
  94. Geherin SA, Fintushel SR, Lee MH, Wilson RP, Patel RT. 94.  et al. 2012. The skin, a novel niche for recirculating B cells. J. Immunol. 188:6027–35 [Google Scholar]
  95. MacPherson GG, Jenkins CD, Stein MJ, Edwards C. 95.  1995. Endotoxin-mediated dendritic cell release from the intestine: characterization of released dendritic cells and TNF dependence. J. Immunol. 154:1317–22 [Google Scholar]
  96. Ulvmar MH, Werth K, Braun A, Kelay P, Hub E. 96.  et al. 2014. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat. Immunol. 15:623–30 [Google Scholar]
  97. Qu C, Edwards EW, Tacke F, Angeli V, Llodra J. 97.  et al. 2004. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J. Exp. Med. 200:1231–41 [Google Scholar]
  98. Das S, Sarrou E, Podgrabinska S, Cassella M, Mungamuri SK. 98.  et al. 2013. Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses. J. Exp. Med. 210:1509–28 [Google Scholar]
  99. Rantakari P, Auvinen K, Jappinen N, Kapraali M, Valtonen J. 99.  et al. 2015. The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes. Nat. Immunol. 16:386–96 [Google Scholar]
  100. Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ. 100.  et al. 2010. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J. Exp. Med. 207:17–27 [Google Scholar]
  101. Shiow LR, Rosen DB, Brdickova N, Xu Y, An J. 101.  et al. 2006. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440:540–44 [Google Scholar]
  102. Angeli V, Ginhoux F, Llodra J, Quemeneur L, Frenette PS. 102.  et al. 2006. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–15 [Google Scholar]
  103. Tan KW, Yeo KP, Wong FH, Lim HY, Khoo KL. 103.  et al. 2012. Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J. Immunol. 188:4065–80 [Google Scholar]
  104. Tan KW, Chong SZ, Wong FH, Evrard M, Tan SM. 104.  et al. 2013. Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood 122:3666–77 [Google Scholar]
  105. Kataru RP, Kim H, Jang C, Choi DK, Koh BI. 105.  et al. 2011. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96–107 [Google Scholar]
  106. Cohen JN, Tewalt EF, Rouhani SJ, Buonomo EL, Bruce AN. 106.  et al. 2014. Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLOS ONE 9:e87740 [Google Scholar]
  107. Park SM, Angel CE, McIntosh JD, Mansell C, Chen CJ. 107.  et al. 2014. Mapping the distinctive populations of lymphatic endothelial cells in different zones of human lymph nodes. PLOS ONE 9:e94781 [Google Scholar]
  108. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ. 108.  et al. 2010. Lymph node–resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 207:681–88 [Google Scholar]
  109. Chang JE, Turley SJ. 109.  2015. Stromal infrastructure of the lymph node and coordination of immunity. Trends Immunol 36:30–39 [Google Scholar]
  110. Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW. 110.  et al. 2014. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J. Immunol. 192:5002–11 [Google Scholar]
  111. Tamburini BA, Burchill MA, Kedl RM. 111.  2014. Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat. Commun. 5:3989 [Google Scholar]
  112. Malhotra D, Fletcher AL, Astarita J, Lukacs-Kornek V, Tayalia P. 112.  et al. 2012. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat. Immunol. 13:499–510 [Google Scholar]
  113. Rouhani SJ, Eccles JD, Tewalt EF, Engelhard VH. 113.  2014. Regulation of T-cell tolerance by lymphatic endothelial cells. J. Clin. Cell Immunol. 5:1000242 [Google Scholar]
  114. Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D. 114.  et al. 2014. Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. J. Exp. Med. 211:1153–66 [Google Scholar]
  115. Kedl R, Finlon J, Tamburini B. 114a.  2016. Contraction of the hypertrophic lymph node and death of lymphatic endothelial cells as a process for antigen exchange Presented at Lymphat. Gordon Res. Conf., Mar. 22, Ventura, CA [Google Scholar]
  116. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C. 115.  et al. 2012. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13:1118–28 [Google Scholar]
  117. Onder L, Narang P, Scandella E, Chai Q, Iolyeva M. 116.  et al. 2012. IL-7-producing stromal cells are critical for lymph node remodeling. Blood 120:4675–83 [Google Scholar]
  118. Miller CN, Hartigan-O'Connor DJ, Lee MS, Laidlaw G, Cornelissen IP. 117.  et al. 2013. IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. Int. Immunol. 25:471–83 [Google Scholar]
  119. Hara T, Shitara S, Imai K, Miyachi H, Kitano S. 118.  et al. 2012. Identification of IL-7-producing cells in primary and secondary lymphoid organs using IL-7-GFP knock-in mice. J. Immunol. 189:1577–84 [Google Scholar]
  120. Shinoda K, Hirahara K, Iinuma T, Ichikawa T, Suzuki AS. 119.  et al. 2016. Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation. PNAS 113:E2842–51 [Google Scholar]
  121. Steinskog ES, Sagstad SJ, Wagner M, Karlsen TV, Yang N. 120.  et al. 2016. Impaired lymphatic function accelerates cancer growth. Oncotarget 7:45789–802 [Google Scholar]
  122. Adair TH, Moffatt DS, Paulsen AW, Guyton AC. 121.  1982. Quantitation of changes in lymph protein concentration during lymph node transit. Am. J. Physiol. 243:H351–59 [Google Scholar]
  123. Hess PR, Rawnsley DR, Jakus Z, Yang Y, Sweet DT. 122.  et al. 2014. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. J. Clin. Investig. 124:273–84 [Google Scholar]
  124. Bertozzi CC, Hess PR, Kahn ML. 123.  2010. Platelets: covert regulators of lymphatic development. Arterioscler. Thromb. Vasc. Biol. 30:2368–71 [Google Scholar]
  125. Thomas SN, Rutkowski JM, Pasquier M, Kuan EL, Alitalo K. 124.  et al. 2012. Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage. J. Immunol. 189:2181–90 [Google Scholar]
  126. Patel KM, Manrique O, Sosin M, Hashmi MA, Poysophon P, Henderson R. 125.  2015. Lymphatic mapping and lymphedema surgery in the breast cancer patient. Gland Surg 4:244–56 [Google Scholar]
  127. Warren S, Sommers SC. 126.  1954. Pathology of regional ileitis and ulcerative colitis. J. Am. Med. Assoc 154189–93 [Google Scholar]
  128. de Souza HS, Fiocchi C. 127.  2016. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13:13–27 [Google Scholar]
  129. Donia MS, Fischbach MA. 128.  2015. Small molecules from the human microbiota. Science 349:1254766 [Google Scholar]
  130. Colombel JF, Watson AJ, Neurath MF. 129.  2008. The 10 remaining mysteries of inflammatory bowel disease. Gut 57:429–33 [Google Scholar]
  131. Dieu-Nosjean MC, Goc J, Giraldo NA, Sautes-Fridman C, Fridman WH. 130.  2014. Tertiary lymphoid structures in cancer and beyond. Trends Immunol 35:571–80 [Google Scholar]
  132. Fonseca DM, Hand TW, Han SJ, Gerner MY, Glatman Zaretsky A. 131.  et al. 2015. Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity. Cell 163:354–66 [Google Scholar]
  133. Scallan JP, Huxley VH. 132.  2010. In vivo determination of collecting lymphatic vessel permeability to albumin: a role for lymphatics in exchange. J. Physiol. 588:243–54 [Google Scholar]
  134. Lochner M, Ohnmacht C, Presley L, Bruhns P, Si-Tahar M. 133.  et al. 2011. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208:125–34 [Google Scholar]
  135. Aldrich MB, Sevick-Muraca EM. 134.  2013. Cytokines are systemic effectors of lymphatic function in acute inflammation. Cytokine 64:362–69 [Google Scholar]
  136. Vitavska O, Edemir B, Wieczorek H. 135.  2016. Putative role of the H+/sucrose symporter SLC45A3 as an osmolyte transporter in the kidney. Pflugers Arch 468:1353–62 [Google Scholar]
  137. Hofmeister LH, Perisic S, Titze J. 136.  2015. Tissue sodium storage: evidence for kidney-like extrarenal countercurrent systems?. Pflugers Arch 467:551–58 [Google Scholar]
  138. Boukens BJ, Christoffels VM. 137.  2012. Popeye proteins: muscle for the aging sinus node. J. Clin. Investig. 122:810–13 [Google Scholar]
  139. Yang Y, Oliver G. 138.  2014. Transcriptional control of lymphatic endothelial cell type specification. Adv. Anat. Embryol. Cell Biol. 214:5–22 [Google Scholar]
  140. Jackson DG. 139.  2003. The lymphatics revisited: new perspectives from the hyaluronan receptor LYVE-1. Trends Cardiovasc. Med. 13:1–7 [Google Scholar]
  141. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G. 140.  et al. 1999. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am. J. Pathol. 154:385–94 [Google Scholar]
  142. Uhrin P, Zaujec J, Breuss JM, Olcaydu D, Chrenek P. 141.  et al. 2010. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 115:3997–4005 [Google Scholar]
  143. Platt N, Gordon S. 142.  2001. Is the class A macrophage scavenger receptor (SR-A) multifunctional? The mouse's tale. J. Clin. Investig. 108:649–54 [Google Scholar]
  144. Harris EN, Weigel JA, Weigel PH. 143.  2008. The human hyaluronan receptor for endocytosis (HARE/Stabilin-2) is a systemic clearance receptor for heparin. J. Biol. Chem. 283:17341–50 [Google Scholar]
  145. Jurisic G, Maby-El Hajjami H, Karaman S, Ochsenbein AM, Alitalo A. 144.  et al. 2012. An unexpected role of semaphorin3A–neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ. Res. 111:426–36 [Google Scholar]
  146. Copeland SJ, Thurston SF, Copeland JW. 145.  2016. Actin- and microtubule-dependent regulation of Golgi morphology by FHDC1. Mol. Biol. Cell 27:260–76 [Google Scholar]
  147. Moore TC. 146.  1984. Modification of lymphocyte traffic by vasoactive neurotransmitter substances. Immunology 52:511–18 [Google Scholar]
  148. Formoso K, Garcia MD, Frasch AC, Scorticati C. 147.  2015. Filopodia formation driven by membrane glycoprotein M6a depends on the interaction of its transmembrane domains. J. Neurochem. 134:499–512 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error