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Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism

Cellular & Molecular Immunology volume 16, pages 165–177 (2019)Cite this article

Abstract

B cells home to the lymph nodes (LNs) via high endothelial venules (HEVs) under the guidance of chemokines, particularly CXCL13. However, as CXCL13 is not directly made in HEVs, the molecular mechanism mediating B-cell homing to LNs has remained unclear. We show here that nuclear factor (NF)-κB-inducing kinase (NIK), a kinase mediating activation of the noncanonical NF-κB pathway, functions in lymphatic endothelial cells (LECs) to regulate B-cell homing to LNs. LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs. The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen. B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells. We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs. Although CCL19 is also expressed in blood endothelial cells (BECs), CXCL13 is not produced in BECs. These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.

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References

  1. Gowans JL. The recirculation of lymphocytes from blood to lymph in the rat. J Physiol 1959; 146: 54–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Girard JP, Springer TA. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol Today 1995; 16: 449–457.

    CAS  PubMed  Google Scholar 

  3. Miyasaka M, Tanaka T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol 2004; 4: 360–370.

    CAS  PubMed  Google Scholar 

  4. Girard JP, Moussion C, Forster R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 2012; 12: 762–773.

    CAS  PubMed  Google Scholar 

  5. von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol 2003; 3: 867–878.

    CAS  PubMed  Google Scholar 

  6. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272: 60–66.

    CAS  PubMed  Google Scholar 

  7. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999; 99: 23–33.

    CAS  PubMed  Google Scholar 

  8. Nakano H, Tamura T, Yoshimoto T, Yagita H, Miyasaka M, Butcher EC et al. Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes. Eur J Immunol 1997; 27: 215–221.

    CAS  PubMed  Google Scholar 

  9. Baekkevold ES, Yamanaka T, Palframan RT, Carlsen HS, Reinholt FP, von Andrian UH et al. The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J Exp Med 2001; 193: 1105–1112.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ebisuno Y, Tanaka T, Kanemitsu N, Kanda H, Yamaguchi K, Kaisho T et al. Cutting edge: the B cell chemokine CXC chemokine ligand 13/B lymphocyte chemoattractant is expressed in the high endothelial venules of lymph nodes and Peyer's patches and affects B cell trafficking across high endothelial venules. J Immunol 2003; 171: 1642–1646.

    CAS  PubMed  Google Scholar 

  11. Forster R, Emrich T, Kremmer E, Lipp M. Expression of the G-protein—coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood 1994; 84: 830–840.

    CAS  PubMed  Google Scholar 

  12. Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999; 144: 789–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 2008; 3: 367–397.

    CAS  PubMed  Google Scholar 

  14. Jackson DG. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS 2004; 112: 526–538.

    CAS  PubMed  Google Scholar 

  15. Kesler CT, Liao S, Munn LL, Padera TP. Lymphatic vessels in health and disease. Wiley Interdiscip Rev Syst Biol Med 2013; 5: 111–124.

    CAS  PubMed  Google Scholar 

  16. Wang Y, Oliver G. Current views on the function of the lymphatic vasculature in health and disease. Genes Dev 2010; 24: 2115–2126.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yeo KP, Angeli V. Bidirectional crosstalk between lymphatic endothelial cell and T cell and its implications in tumor immunity. Front Immunol 2017; 8: 83.

    PubMed  PubMed Central  Google Scholar 

  18. Sun SC. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol 2017; 17: 545–558.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sun SC. The noncanonical NF-kappaB pathway. Immunol Rev 2012; 246: 125–140.

    PubMed  PubMed Central  Google Scholar 

  20. Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 2017; 17: 545–558.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol 2010; 10: 664–674.

    CAS  PubMed  Google Scholar 

  22. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001; 293: 1495–1499.

    CAS  PubMed  Google Scholar 

  23. Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7: 401–409.

    CAS  PubMed  Google Scholar 

  24. Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet 1999; 22: 74–77.

    CAS  PubMed  Google Scholar 

  25. Brightbill HD, Jackman JK, Suto E, Kennedy H, Jones C 3rd, Chalasani S et al. Conditional deletion of NF-kappaB-inducing kinase (NIK) in adult mice disrupts mature B cell survival and activation. J Immunol 2015; 195: 953–964.

    CAS  PubMed  Google Scholar 

  26. Maijer KI, Noort AR, de Hair MJ, van der Leij C, van Zoest KP, Choi IY et al. Nuclear factor-kappaB-inducing kinase is expressed in synovial endothelial cells in patients with early arthritis and correlates with markers of inflammation: a prospective cohort study. J Rheumatol 2015; 42: 1573–1581.

    CAS  PubMed  Google Scholar 

  27. Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ, Pappu R et al. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J Exp Med 2010; 207: 17–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Moussion C, Girard JP. Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 2011; 479: 542–546.

    CAS  PubMed  Google Scholar 

  29. Allan RS, Waithman J, Bedoui S, Jones CM, Villadangos JA, Zhan Y et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 2006; 25: 153–162.

    CAS  PubMed  Google Scholar 

  30. Escobedo N, Proulx ST, Karaman S, Dillard ME, Johnson N, Detmar M et al. Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice. JCI Insight 2016; 1: e85096.

    PubMed  PubMed Central  Google Scholar 

  31. Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol 2007; 8: 1255–1265.

    CAS  PubMed  Google Scholar 

  32. Thomas MD, Srivastava B, Allman D. Regulation of peripheral B cell maturation. Cell Immunol 2006; 239: 92–102.

    CAS  PubMed  Google Scholar 

  33. Fletcher AL, Malhotra D, Acton SE, Lukacs-Kornek V, Bellemare-Pelletier A, Curry M et al. Reproducible isolation of lymph node stromal cells reveals site-dependent differences in fibroblastic reticular cells. Front Immunol 2011; 2: 35.

    PubMed  PubMed Central  Google Scholar 

  34. Martin-Fontecha A, Lanzavecchia A, Sallusto F. Dendritic cell migration to peripheral lymph nodes. Handb Exp Pharmacol 2009, 31–49.

  35. Forster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 2008; 8: 362–371.

    PubMed  Google Scholar 

  36. Cyster JG. Leukocyte migration: scent of the T zone. Curr Biol 2000; 10: R30–R33.

    CAS  PubMed  Google Scholar 

  37. Leon B, Ballesteros-Tato A, Browning JL, Dunn R, Randall TD, Lund FE. Regulation of T(H)2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells. Nat Immunol 2012; 13: 681–690.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Saeki H, Wu MT, Olasz E, Hwang ST. A migratory population of skin-derived dendritic cells expresses CXCR5, responds to B lymphocyte chemoattractant in vitro, and co-localizes to B cell zones in lymph nodes in vivo. Eur J Immunol 2000; 30: 2808–2814.

    CAS  PubMed  Google Scholar 

  39. Yu P, Wang Y, Chin RK, Martinez-Pomares L, Gordon S, Kosco-Vibois MH et al. B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion. J Immunol 2002; 168: 5117–5123.

    CAS  PubMed  Google Scholar 

  40. Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 2004; 21: 279–288.

    CAS  PubMed  Google Scholar 

  41. De Silva NS, Klein U. Dynamics of B cells in germinal centres. Nat Rev Immunol 2015; 15: 137–148.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yamada T, Mitani T, Yorita K, Uchida D, Matsushima A, Iwamasa K et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase. J Immunol 2000; 165: 804–812.

    CAS  PubMed  Google Scholar 

  43. Shinkura R, Matsuda F, Sakiyama T, Tsubata T, Hiai H, Paumen M et al. Defects of somatic hypermutation and class switching in alymphoplasia (aly) mutant mice. Int Immunol 1996; 8: 1067–1075.

    CAS  PubMed  Google Scholar 

  44. Miyawaki S, Nakamura Y, Suzuka H, Koba M, Yasumizu R, Ikehara S et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur J Immunol 1994; 24: 429–434.

    CAS  PubMed  Google Scholar 

  45. Karrer U, Althage A, Odermatt B, Hengartner H, Zinkernagel RM. Immunodeficiency of alymphoplasia mice (aly/aly) in vivo: structural defect of secondary lymphoid organs and functional B cell defect. Eur J Immunol 2000; 30: 2799–2807.

    CAS  PubMed  Google Scholar 

  46. Rosen SD. Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 2004; 22: 129–156.

    CAS  PubMed  Google Scholar 

  47. Mueller SN, Germain RN. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol 2009; 9: 618–629.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci USA 1998; 95: 258–263.

    CAS  PubMed  Google Scholar 

  49. Luther SA, Tang HL, Hyman PL, Farr AG, Cyster JG. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc Natl Acad Sci USA 2000; 97: 12694–12699.

    CAS  PubMed  Google Scholar 

  50. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 1998; 391: 799–803.

    CAS  PubMed  Google Scholar 

  51. Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 2006; 25: 989–1001.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, Makris C et al. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 2002; 17: 525–535.

    CAS  PubMed  Google Scholar 

  53. Ware CF. Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 2005; 23: 787–819.

    CAS  PubMed  Google Scholar 

  54. Kumar V, Dasoveanu DC, Chyou S, Tzeng TC, Rozo C, Liang Y et al. A dendritic-cell-stromal axis maintains immune responses in lymph nodes. Immunity 2015; 42: 719–730.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K et al. In vivo analysis of dendritic cell development and homeostasis. Science 2009; 324: 392–397.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Seth S, Oberdorfer L, Hyde R, Hoff K, Thies V, Worbs T et al. CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. J Immunol 2011; 186: 3364–3372.

    CAS  PubMed  Google Scholar 

  57. Marsland BJ, Battig P, Bauer M, Ruedl C, Lassing U, Beerli RR et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity 2005; 22: 493–505.

    CAS  PubMed  Google Scholar 

  58. Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 1999; 189: 451–460.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Genentech Inc. for providing the NIK-flox mice. This work was supported by grants from the National Institutes of Health (GM84459, AI057555, AI104519 and AI64639). This study also used the NIH/NCI-supported resources under award number P30CA016672 at The MD Anderson Cancer Center. SZ was supported by a scholarship from the China Scholarship Council (CSC) under the Grant CSC 201506210393. We also thank Professor Wei He for his support.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA

    Jie Yang, Siya Zhang, Lingyun Zhang, Xiaoping Xie, Hui Wang, Zuliang Jie, Meidi Gu, Jin-Young Yang, Xuhong Cheng & Shao-Cong Sun

  2. Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, 100005, Beijing, China

    Siya Zhang

  3. The University of Texas Graduate School of Biomedical Sciences, 77030, Houston, TX, USA

    Shao-Cong Sun

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  1. Jie Yang
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JY and SZ designed and performed the experiments, and JY prepared the figures and wrote the manuscript. LZ, XX, HW, ZJ, MG, J-YY and XC contributed to the performance of the experiments. S-CS supervised the work and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Yang, J., Zhang, S., Zhang, L. et al. Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism. Cell Mol Immunol 16, 165–177 (2019). https://doi.org/10.1038/cmi.2017.167

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