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Lymph node stromal cells: cartographers of the immune system

Abstract

Lymph nodes (LNs) are strategically positioned at dedicated sites throughout the body to facilitate rapid and efficient immunity. Central to the structural integrity and framework of LNs, and the recruitment and positioning of leukocytes therein, are mesenchymal and endothelial lymph node stromal cells (LNSCs). Advances in the last decade have expanded our understanding and appreciation of LNSC heterogeneity, and the role they play in coordinating immunity has grown rapidly. In this review, we will highlight the functional contributions of distinct stromal cell populations during LN development in maintaining immune homeostasis and tolerance and in the activation and control of immune responses.

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Fig. 1: Roles of endothelial and mesenchymal cells during initial steps of LN organogenesis.
Fig. 2: Stromal cell heterogeneity and function during LN homeostasis.
Fig. 3: Fibroblastic reticular cell remodeling and proliferation during reactive LN expansion.
Fig. 4: Stromal cell control of adaptive immune responses.

References

  1. Hoorweg, K. & Cupedo, T. Development of human lymph nodes and Peyer’s patches. Semin. Immunol. 20, 164–170 (2008).

    CAS  PubMed  Google Scholar 

  2. Trepel, F. Number and distribution of lymphocytes in man. A critical analysis. Klin. Wochenschr. 52, 511–515 (1974).

    CAS  PubMed  Google Scholar 

  3. Van den Broeck, W., Derore, A. & Simoens, P. Anatomy and nomenclature of murine lymph nodes: descriptive study and nomenclatory standardization in BALB/cAnNCrl mice. J. Immunol. Methods 312, 12–19 (2006).

    PubMed  Google Scholar 

  4. Cupedo, T. et al. Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes. J. Immunol. 173, 2968–2975 (2004).

    CAS  PubMed  Google Scholar 

  5. Boos, M. D., Yokota, Y., Eberl, G. & Kee, B. L. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 204, 1119–1130 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2004).

    CAS  PubMed  Google Scholar 

  7. Mueller, C. G. & Hess, E. Emerging functions of RANKL in lymphoid tissues. Front. Immunol. 3, 261 (2012).

    PubMed  PubMed Central  Google Scholar 

  8. Mebius, R. E. Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3, 292–303 (2003).

    CAS  PubMed  Google Scholar 

  9. Onder, L. et al. Lymphatic endothelial cells control initiation of lymph node organogenesis. Immunity 47, 80–92.e4 (2017).

    CAS  PubMed  Google Scholar 

  10. Bendolan, A. & Caamaño, J. H. Mesenchymal cell differentiation during lymph node organogenesis. Front. Immunol. 3, 381 (2012).

    Google Scholar 

  11. Yoshida, H. et al. Different cytokines induce surface lymphotoxin-αβ on IL-7 receptor-α cells that differentially engender lymph nodes and Peyer’s patches. Immunity 17, 823–833 (2002).

    CAS  PubMed  Google Scholar 

  12. Luther, S. A., Ansel, K. M. & Cyster, J. G. Overlapping roles of CXCL13, interleukin 7 receptor α, and CCR7 ligands in lymph node development. J. Exp. Med. 197, 1191–1198 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Vondenhoff, M. F. et al. LTβR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen. J. Immunol. 182, 5439–5445 (2009).

    CAS  PubMed  Google Scholar 

  14. Mueller, C. G. Emerging functions of RANKL in lymphoid tissues. Front. Immunol. 3, 261 (2012).

    PubMed  PubMed Central  Google Scholar 

  15. Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    CAS  PubMed  Google Scholar 

  16. Bénézech, C. et al. Ontogeny of stromal organizer cells during lymph node development. J. Immunol. 184, 4521–4530 (2010).

    PubMed  Google Scholar 

  17. White, A. et al. Lymphotoxin a-dependent and -independent signals regulate stromal organizer cell homeostasis during lymph node organogenesis. Blood 110, 1950–1959 (2007).

    CAS  PubMed  Google Scholar 

  18. Banks, T. A. et al. Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155, 1685–1693 (1995).

    CAS  PubMed  Google Scholar 

  19. De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).

    PubMed  Google Scholar 

  20. Alimzhanov, M. B. et al. Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice. Proc. Natl Acad. Sci. USA 94, 9302–9307 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fütterer, A., Mink, K., Luz, A., Kosco-Vilbois, M. H. & Pfeffer, K. The lymphotoxin β receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9, 59–70 (1998).

    PubMed  Google Scholar 

  22. Koni, P. A. et al. Distinct roles in lymphoid organogenesis for lymphotoxins α and β revealed in lymphotoxin β-deficient mice. Immunity 6, 491–500 (1997).

    CAS  PubMed  Google Scholar 

  23. Miyawaki, S. et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 24, 429–434 (1994).

    CAS  PubMed  Google Scholar 

  24. Sabin, F. R. The lymphatic system in human embryos, with a consideration of the morphology of the system as a whole. Am. J. Anat. 9, 43–91 (1909).

    Google Scholar 

  25. Vondenhoff, M. F. et al. Lymph sacs are not required for the initiation of lymph node formation. Development 136, 29–34 (2009).

    CAS  PubMed  Google Scholar 

  26. Bénézech, C. et al. Lymphotoxin-β receptor signaling through NF-κB2-RelB pathway reprograms adipocyte precursors as lymph node stromal cells. Immunity 37, 721–734 (2012).

    PubMed  Google Scholar 

  27. van de Pavert, S. A. et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10, 1193–1199 (2009).

    PubMed  PubMed Central  Google Scholar 

  28. Chai, Q. et al. Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity. Immunity 38, 1013–1024 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Onder, L. et al. Endothelial cell-specific lymphotoxin-β receptor signaling is critical for lymph node and high endothelial venule formation. J. Exp. Med. 210, 465–473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bovay, E. et al. Multiple roles of lymphatic vessels in peripheral lymph node development. J. Exp. Med. 215, 2760–2777 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rennert, P. D., James, D., Mackay, F., Browning, J. L. & Hochman, P. S. Lymph node genesis is induced by signaling through the lymphotoxin β receptor. Immunity 9, 71–79 (1998).

    CAS  PubMed  Google Scholar 

  32. Lee, Y. G. & Koh, G. Y. Coordinated lymphangiogenesis is critical in lymph node development and maturation. Dev. Dyn. 245, 1189–1197 (2016).

    CAS  PubMed  Google Scholar 

  33. Rantakari, P. et al. The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes. Nat. Immunol. 16, 386–396 (2015).

    CAS  PubMed  Google Scholar 

  34. Mondor, I. et al. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche. Immunity 50, 1453–1466.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Takeda, A. et al. Single-cell survey of human lymphatics unveils marked endothelial cell heterogeneity and mechanisms of homing for neutrophils. Immunity 51, 561–572.e5 (2019).

    CAS  PubMed  Google Scholar 

  36. Anderson, A. O. & Shaw, S. T cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node. Semin. Immunol. 5, 271–282 (1993).

    CAS  PubMed  Google Scholar 

  37. Lee, M. et al. Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nat. Immunol. 15, 982–995 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Moussion, C. & Girard, J.-P. Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479, 542–546 (2011).

    CAS  PubMed  Google Scholar 

  39. Girard, J.-P., Moussion, C. & Förster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12, 762–773 (2012).

    CAS  PubMed  Google Scholar 

  40. Hendriks, H. R., Duijvestijn, A. M. & Kraal, G. Rapid decrease in lymphocyte adherence to high endothelial venules in lymph nodes deprived of afferent lymphatic vessels. Eur. J. Immunol. 17, 1691–1695 (1987).

    CAS  PubMed  Google Scholar 

  41. Aguzzi, A., Kranich, J. & Krautler, N. J. Follicular dendritic cells: origin, phenotype, and function in health and disease. Trends Immunol. 35, 105–113 (2014).

    CAS  PubMed  Google Scholar 

  42. Katakai, T. Marginal reticular cells: a stromal subset directly descended from the lymphoid tissue organizer. Front. Immunol. 3, 200 (2012).

    PubMed  PubMed Central  Google Scholar 

  43. Perez-Shibayama, C., Gil-Cruz, C. & Ludewig, B. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses. Immunol. Rev. 289, 31–41 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Le Hir, M. et al. Tumor necrosis factor receptor-1 signaling is required for differentiation of follicular dendritic cells, germinal center formation, and full antibody responses. J. Inflamm. 47, 76–80 (1995).

    PubMed  Google Scholar 

  45. Koning, J. J. et al. Nestin-expressing precursors give rise to both endothelial as well as nonendothelial lymph node stromal cells. J. Immunol. 197, 2686–2694 (2016).

    CAS  PubMed  Google Scholar 

  46. Denton, A. E., Roberts, E. W., Linterman, M. A. & Fearon, D. T. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proc. Natl Acad. Sci. USA 111, 12139–12144 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Denton, A. E., Carr, E. J., Magiera, L. P., Watts, A. J. B. & Fearon, D. T. Embryonic FAP+ lymphoid tissue organizer cells generate the reticular network of adult lymph nodes. J. Exp. Med. 216, 2242–2252 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Castagnaro, L. et al. Nkx2-5+Islet1+ mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity. Immunity 38, 782–791 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Schaeuble, K. et al. Perivascular fibroblasts of the developing spleen act as LTα1β2-dependent precursors of both T and B zone organizer cells. Cell Rep. 21, 2500–2514 (2017).

    CAS  PubMed  Google Scholar 

  50. Cheng, H.-W. et al. Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp. Nat. Commun. 10, 1739 (2019).

    PubMed  PubMed Central  Google Scholar 

  51. Novkovic, M. et al. Topological small-world organization of the fibroblastic reticular cell network determines lymph node functionality. PLoS Biol. 14, e1002515 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Astarita, J. L. et al. The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat. Immunol. 16, 75–84 (2015).

    CAS  PubMed  Google Scholar 

  53. Herzog, B. H. et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502, 105–109 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Acton, S. E. et al. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 37, 276–289 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424–433 (2002).

    CAS  PubMed  Google Scholar 

  56. Luther, S. A., Tang, H. L., Hyman, P. L., Farr, A. G. & Cyster, J. G. 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 97, 12694–12699 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ulvmar, M. H. et al. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat. Immunol. 15, 623–630 (2014).

    CAS  PubMed  Google Scholar 

  58. Bajénoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).

    PubMed  PubMed Central  Google Scholar 

  59. Katakai, T., Hara, T., Sugai, M., Gonda, H. & Shimizu, A. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. J. Exp. Med. 200, 783–795 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kumar, V. et al. A dendritic-cell-stromal axis maintains immune responses in lymph nodes. Immunity 42, 719–730 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zeng, M. et al. Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution. Blood 120, 1856–1867 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Saito, Y. et al. SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen. Proc. Natl Acad. Sci. USA 114, E10151–E10160 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Roozendaal, R. et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity 30, 264–276 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gretz, J. E., Norbury, C. C., Anderson, A. O., Proudfoot, A. E. & Shaw, S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J. Exp. Med. 192, 1425–1440 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sixt, M. et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19–29 (2005).

    CAS  PubMed  Google Scholar 

  66. Thierry, G. R. et al. The conduit system exports locally secreted IgM from lymph nodes. J. Exp. Med. 215, 2972–2983 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chang, J. E., Buechler, M. B., Gressier, E., Turley, S. J. & Carroll, M. C. Mechanosensing by Peyer’s patch stroma regulates lymphocyte migration and mucosal antibody responses. Nat. Immunol. 20, 1506–1516 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).

    CAS  PubMed  Google Scholar 

  69. Onder, L. et al. IL-7-producing stromal cells are critical for lymph node remodeling. Blood 120, 4675–4683 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Iolyeva, M. et al. Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage. Blood 122, 2271–2281 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Cremasco, V. et al. B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat. Immunol. 15, 973–981 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang, X. et al. Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J. Exp. Med. 208, 2497–2510 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Heesters, B. A., Myers, R. C. & Carroll, M. C. Follicular dendritic cells: dynamic antigen libraries. Nat. Rev. Immunol. 14, 495–504 (2014).

    CAS  PubMed  Google Scholar 

  74. Hoorweg, K. et al. A stromal cell niche for human and mouse type 3 innate lymphoid cells. J. Immunol. 195, 4257–4263 (2015).

    CAS  PubMed  Google Scholar 

  75. Cordeiro, O. G. et al. Integrin-alpha IIb identifies murine lymph node lymphatic endothelial cells responsive to RANKL. PLoS One 11, e0151848 (2016).

    PubMed  PubMed Central  Google Scholar 

  76. Camara, A. et al. Lymph node mesenchymal and endothelial stromal cells cooperate via the RANK-RANKL cytokine axis to shape the sinusoidal macrophage niche. Immunity 50, 1467–1481.e6 (2019).

    CAS  PubMed  Google Scholar 

  77. Magri, G. et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat. Immunol. 15, 354–364 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Fasnacht, N. et al. Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J. Exp. Med. 211, 2265–2279 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. Malhotra, D. et al. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat. Immunol. 13, 499–510 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yamazaki, T. & Mukouyama, Y.-S. Tissue specific origin, development, and pathological perspectives of pericytes. Front. Cardiovasc. Med. 5, 78 (2018).

    PubMed  PubMed Central  Google Scholar 

  81. Krautler, N. J. et al. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell 150, 194–206 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sitnik, K. M. et al. Context-dependent development of lymphoid stroma from adult CD34+ adventitial progenitors. Cell Rep. 14, 2375–2388 (2016).

    CAS  PubMed  Google Scholar 

  83. Rodda, L. B. et al. Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity 48, 1014–1028.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee, J.-W. et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol. 8, 181–190 (2007).

    CAS  PubMed  Google Scholar 

  85. Fletcher, A. L. et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J. Exp. Med. 207, 689–697 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Cohen, J. N. et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 207, 681–688 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Fletcher, A. L., Malhotra, D. & Turley, S. J. Lymph node stroma broaden the peripheral tolerance paradigm. Trends Immunol. 32, 12–18 (2011).

    CAS  PubMed  Google Scholar 

  88. Yip, L. et al. Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes. Nat. Immunol. 10, 1026–1033 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Cohen, J. N. et al. Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLoS One 9, e87740 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Dubrot, J. et al. Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. J. Exp. Med. 211, 1153–1166 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Rouhani, S. J. et al. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat. Commun. 6, 6771 (2015).

    CAS  PubMed  Google Scholar 

  92. Baptista, A. P. et al. Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. Elife 3, e04433 (2014).

    PubMed Central  Google Scholar 

  93. Pezoldt, J. et al. Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes. Nat. Commun. 9, 3903 (2018).

    PubMed  PubMed Central  Google Scholar 

  94. Pasztoi, M. et al. Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3+ regulatory T cells. Eur. J. Immunol. 47, 2142–2152 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Cording, S. et al. The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes. Mucosal Immunol. 7, 359–368 (2014).

    CAS  PubMed  Google Scholar 

  96. Yang, C.-Y. et al. Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes. Proc. Natl Acad. Sci. USA 111, E109–E118 (2014).

    CAS  PubMed  Google Scholar 

  97. Tan, K. W. et al. Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J. Immunol. 188, 4065–4080 (2012).

    CAS  PubMed  Google Scholar 

  98. Tomei, A. A., Siegert, S., Britschgi, M. R., Luther, S. A. & Swartz, M. A. Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. J. Immunol. 183, 4273–4283 (2009).

    CAS  PubMed  Google Scholar 

  99. Acton, S. E. et al. Dendritic cells control fibroblastic reticular network tension and lymph node expansion. Nature 514, 498–502 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Gregory, J. L. et al. Infection programs sustained lymphoid stromal cell responses and shapes lymph node remodeling upon secondary challenge. Cell Rep. 18, 406–418 (2017).

    CAS  PubMed  Google Scholar 

  101. Mueller, S. N. et al. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl Acad. Sci. USA 104, 15430–15435 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Scandella, E. et al. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat. Immunol. 9, 667–675 (2008).

    CAS  PubMed  Google Scholar 

  103. Riedel, A., Shorthouse, D., Haas, L., Hall, B. A. & Shields, J. Tumor-induced stromal reprogramming drives lymph node transformation. Nat. Immunol. 17, 1118–1127 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Suenaga, F. et al. Loss of lymph node fibroblastic reticular cells and high endothelial cells is associated with humoral immunodeficiency in mouse graft-versus-host disease. J. Immunol. 194, 398–406 (2015).

    CAS  PubMed  Google Scholar 

  105. Dertschnig, S. et al. Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity. J. Clin. Invest. https://doi.org/10.1172/JCI133102 (2020).

  106. Yang, C.-Y. et al. Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes. Proc. Natl Acad. Sci. USA 111, E109–18 (2014).

    CAS  PubMed  Google Scholar 

  107. Benahmed, F. et al. Multiple CD11c+ cells collaboratively express IL-1β to modulate stromal vascular endothelial growth factor and lymph node vascular-stromal growth. J. Immunol. 192, 4153–4163 (2014).

    CAS  PubMed  Google Scholar 

  108. Dubey, L. K. et al. Lymphotoxin-dependent B cell-FRC crosstalk promotes de novo follicle formation and antibody production following intestinal helminth infection. Cell Rep. 15, 1527–1541 (2016).

    CAS  PubMed  Google Scholar 

  109. Majumder, S. et al. IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival. Nat. Immunol. 20, 534–545 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Dasoveanu, D. C., Shipman, W. D., Chia, J. J., Chyou, S. & Lu, T. T. Regulation of lymph node vascular–stromal compartment by dendritic cells. Trends Immunol. 37, 764–777 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gregory, J. L. et al. Infection programs sustained lymphoid stromal cell responses and shapes lymph node remodeling upon secondary challenge. Cell Rep. 18, 406–418 (2017).

    CAS  PubMed  Google Scholar 

  112. Lukacs-Kornek, V. et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat. Immunol. 12, 1096–1104 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Siegert, S. et al. Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS One 6, e27618 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Knoblich, K. et al. The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation. PLoS Biol. 16, e2005046 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. Fletcher, A. L. et al. Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis. Sci. Transl. Med. 6, 249ra109 (2014).

    PubMed  PubMed Central  Google Scholar 

  116. Abe, J. et al. Lymph node stromal cells negatively regulate antigen-specific CD4+ T cell responses. J. Immunol. 193, 1636–1644 (2014).

    CAS  PubMed  Google Scholar 

  117. Brown, F. D. et al. Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling. Nat. Immunol. 20, 1668–1680 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Gil-Cruz, C. et al. Fibroblastic reticular cells regulate intestinal inflammation via IL-15-mediated control of group 1 ILCs. Nat. Immunol. 17, 1388–1396 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Disson, O. et al. Peyer’s patch myeloid cells infection by Listeria signals through gp38+ stromal cells and locks intestinal villus invasion. J. Exp. Med. 215, 2936–2954 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Li, C. et al. Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity. Sci. Immunol. 4, eaax1027 (2019).

    CAS  PubMed  Google Scholar 

  121. Jarjour, M. et al. Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells. J. Exp. Med. 211, 1109–1122 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Wu, Y. et al. IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation. Int. Immunol. 21, 745–756 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Allen, C. D. C., Okada, T. & Cyster, J. G. Germinal-center organization and cellular dynamics. Immunity 27, 190–202 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Bajénoff, M. & Germain, R. N. B-cell follicle development remodels the conduit system and allows soluble antigen delivery to follicular dendritic cells. Blood 114, 4989–4997 (2009).

    PubMed  PubMed Central  Google Scholar 

  125. Allen, C. D. C. & Cyster, J. G. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Semin. Immunol. 20, 14–25 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Mionnet, C. et al. Identification of a new stromal cell type involved in the regulation of inflamed B cell follicles. PLoS Biol. 11, e1001672 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Allen, C. D. C. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943–952 (2004).

    CAS  PubMed  Google Scholar 

  128. Bannard, O. et al. Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection. Immunity 39, 912–924 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Rodda, L. B., Bannard, O., Ludewig, B., Nagasawa, T. & Cyster, J. G. Phenotypic and morphological properties of germinal center dark zone Cxcl12-expressing reticular cells. J. Immunol. 195, 4781–4791 (2015).

    CAS  PubMed  Google Scholar 

  130. Huang, H.-Y. et al. Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis. Proc. Natl Acad. Sci. USA 115, E6826–E6835 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang, Y. et al. Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells. J. Exp. Med. 215, 1227–1243 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Buckley, C. D., Barone, F., Nayar, S., Bénézech, C. & Caamaño, J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu. Rev. Immunol. 33, 715–745 (2015).

    CAS  PubMed  Google Scholar 

  133. Hjelmström, P. et al. Lymphoid tissue homing chemokines are expressed in chronic inflammation. Am. J. Pathol. 156, 1133–1138 (2000).

    PubMed  PubMed Central  Google Scholar 

  134. Jones, G. W., Hill, D. G. & Jones, S. A. Understanding immune cells in tertiary lymphoid organ development: it is all starting to come together. Front. Immunol. 7, 401 (2016).

    PubMed  PubMed Central  Google Scholar 

  135. GeurtsvanKessel, C. H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inlammation. Front. Immunol. 7, 477 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. Ruddle, N. H. High endothelial venules and lymphatic vessels in tertiary lymphoid organs: characteristics, functions, and regulation. Front. Immunol. 7, 491 (2016).

    PubMed  PubMed Central  Google Scholar 

  138. Halle, S. et al. Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. J. Exp. Med. 206, 2593–2601 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Humby, F. et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 6, e1 (2009).

    PubMed  PubMed Central  Google Scholar 

  140. Nacionales, D. C. et al. B cell proliferation, somatic hypermutation, class switch recombination, and autoantibody production in ectopic lymphoid tissue in murine lupus. J. Immunol. 182, 4226–4236 (2009).

    CAS  PubMed  Google Scholar 

  141. Grewal, J. S. et al. Salivary glands act as mucosal inductive sites via the formation of ectopic germinal centers after site-restricted MCMV infection. FASEB J. 25, 1680–1696 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208, 125–134 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Grogan, J. L. & Ouyang, W. A role for Th17 cells in the regulation of tertiary lymphoid follicles. Eur. J. Immunol. 42, 2255–2262 (2012).

    CAS  PubMed  Google Scholar 

  144. Furtado, G. C. et al. TNFα-dependent development of lymphoid tissue in the absence of RORγt+ lymphoid tissue inducer cells. Mucosal Immunol. 7, 602–614 (2014).

    CAS  PubMed  Google Scholar 

  145. Pikor, N. B. et al. Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity 43, 1160–1173 (2015).

    CAS  PubMed  Google Scholar 

  146. Barone, F. et al. IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc. Natl Acad. Sci. USA 112, 11024–11029 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. 216, 621–637 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Nayar, S. et al. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc. Natl Acad. Sci. USA 116, 13490–13497 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Fleige, H. et al. IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs. J. Exp. Med. 211, 643–651 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Astorri, E. et al. Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets. J. Immunol. 185, 3359–3368 (2010).

    CAS  PubMed  Google Scholar 

  152. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    CAS  PubMed  Google Scholar 

  153. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    CAS  PubMed  Google Scholar 

  155. Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).

    PubMed  Google Scholar 

  156. Goc, J. et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 74, 705–715 (2014).

    CAS  PubMed  Google Scholar 

  157. Germain, C. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am. J. Respir. Crit. Care Med. 189, 832–844 (2014).

    CAS  PubMed  Google Scholar 

  158. Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).

    CAS  PubMed  Google Scholar 

  159. Cottrell, T. R. et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann. Oncol. 29, 1853–1860 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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Krishnamurty, A.T., Turley, S.J. Lymph node stromal cells: cartographers of the immune system. Nat Immunol 21, 369–380 (2020). https://doi.org/10.1038/s41590-020-0635-3

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