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  • Review Article
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CCR7 and its ligands: balancing immunity and tolerance

Nature Reviews Immunology volume 8, pages 362–371 (2008)Cite this article

Key Points

  • Chemokines are a large family of chemotactic cytokines that regulate immune-cell trafficking. The chemokines CC-chemokine ligand 19 (CCL19) and CCL21 are ligands for the CC-chemokine receptor 7 (CCR7).

  • CCR7 is expressed by B cells, mature dendritic cells (DCs) and by several T-cell sub-populations including naive, regulatory and central memory T cells. In non-lymphoid organs CCR7 ligands are expressed on the initial segments of lymphatic vessels. In lymphoid organs they are present on high endothelial venules (HEVs) as well as on various populations of spleen, lymph node and thymic stromal cells.

  • CCR7 and its ligands have a key role in lymphocyte and DC homing to the lymph nodes and intestinal Peyer's patches. In a naturally occurring mouse mutant, paucity of lymph-node T cells (plt/plt), CCL19 and CCL21 are absent in lymphoid organs, whereas one variant of CCL21 is still expressed in non-lymphoid organs. In CCR7-deficient and plt/plt mice, T cells are impaired in lymph-node homing via high endothelial venules. Furthermore, in Ccr7−/− mice, DCs fail to enter initial afferent lymphatic vessels following inflammatory stimuli. Therefore, lymph nodes of CCR7-deficient mice are devoid of naive and regulatory T cells and immunity-inducing DCs. Owing to impaired homing of T cells and DCs, CCR7-deficient and plt/plt mice show delayed immune responses at sites where antigen is limited.

  • CCR7 deficiency also impedes the steady-state migration of DCs from non-lymphoid organs, such as the intestine and lung, into the draining lymph nodes. Such migration of DCs that are laden with innocuous antigen, however, is required for the induction of peripheral tolerance. Within secondary lymphoid organs these DCs present food or environmental antigens to reactive T cells, which leads to their anergy, deletion or conversion into regulatory T cells. Owing to impaired homing of T cells and tolerance-inducing DCs to secondary lymphoid organs, CCR7-deficient mice do not develop tolerance to harmless environmental antigens.

  • The paracortical area of lymph nodes is the major site of the suppressive activity of natural regulatory T cells. In CCR7-deficient mice, regulatory T cells show impaired homing to this location and therefore have a profound defect of their in vivo function. CCR7 and its ligands are also essentially involved in thymus organization, T-cell development and negative selection.

Abstract

A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.

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Figure 1: CCR7 in the induction of tolerance to inhaled antigens.
Figure 2: CCR7 in function of regulatory T cells.
Figure 3: CCR7 in thymocyte migration.

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References

  1. Rot, A. & von Andrian, U. H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol. 22, 891–928 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Yoshida, R. et al. Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J. Biol. Chem. 273, 7118–7122 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Gunn, M. D. et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl Acad. Sci. USA 95, 258–263 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stein, J. V. et al. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J. Exp. Med. 191, 61–76 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Friedman, R. S., Jacobelli, J. & Krummel, M. F. Surface-bound chemokines capture and prime T cells for synapse formation. Nature Immunol. 7, 1101–1108 (2006).

    Article  CAS  Google Scholar 

  6. Kerjaschki, D. Lymphatic neoangiogenesis in human neoplasia and transplantation as experiments of nature. BANTAO J. 4, 60–61 (2006).

    Google Scholar 

  7. Vassileva, G. et al. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190, 1183–1188 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nakano, H. & Gunn, M. D. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166, 361–369 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Carlsen, H. S., Haraldsen, G., Brandtzaeg, P. & Baekkevold, E. S. Disparate lymphoid chemokine expression in mice and men: no evidence of CCL21 synthesis by human high endothelial venules. Blood 106, 444–446 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nature Immunol. 8, 1255–1265 (2007). This study shows that fibroblast reticular cells support the intranodal migration of lymphocytes in peripheral lymph nodes. In agreement with this data, reference 41 demonstrates that a subtype of reticular cells express CCL19, CCL21 and IL-7, which support the survival of lymphocytes migrating in the lymph node T-cell zone.

    Article  CAS  Google Scholar 

  12. Sallusto, F. et al. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur. J. Immunol. 29, 1617–1625 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Misslitz, A. et al. Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200, 481–491 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002).

    Article  PubMed  Google Scholar 

  16. Sallusto, F., Lenig, D., Förster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Szanya, V., Ermann, J., Taylor, C., Holness, C. & Fathman, C. G. The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J. Immunol. 169, 2461–2465 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Bardi, G., Lipp, M., Baggiolini, M. & Loetscher, P. The T cell chemokine receptor CCR7 is internalized on stimulation with ELC, but not with SLC. Eur. J. Immunol. 31, 3291–3297 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Kohout, T. A. et al. Differential desensitization, receptor phosphorylation, β-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J. Biol. Chem. 279, 23214–23222 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Gosling, J. et al. Cutting edge: identification of a novel chemokine receptor that binds dendritic cell- and T cell-active chemokines including ELC, SLC, and TECK. J. Immunol. 164, 2851–2856 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Comerford, I., Milasta, S., Morrow, V., Milligan, G. & Nibbs, R. The chemokine receptor CCX-CKR mediates effective scavenging of CCL19 in vitro. Eur. J. Immunol. 36, 1904–1916 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Heinzel, K., Benz, C. & Bleul, C. C. A silent chemokine receptor regulates steady-state leukocyte homing in vivo. Proc. Natl Acad. Sci. USA 104, 8421–8426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Förster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    Article  PubMed  Google Scholar 

  25. Debes, G. F. et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nature Immunol. 6, 889–894 (2005).

    Article  CAS  Google Scholar 

  26. Bromley, S. K., Thomas, S. Y. & Luster, A. D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nature Immunol. 6, 895–901 (2005).

    Article  CAS  Google Scholar 

  27. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Dieu, M. C. et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373–386 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sozzani, S. et al. Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J. Immunol. 161, 1083–1086 (1998).

    CAS  PubMed  Google Scholar 

  30. Yanagihara, S., Komura, E., Nagafune, J., Watarai, H. & Yamaguchi, Y. EBI1/CCR7 is a new member of dendritic cell chemokine receptor that is up-regulated upon maturation. J. Immunol. 161, 3096–3102 (1998).

    CAS  PubMed  Google Scholar 

  31. Hintzen, G. et al. Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J. Immunol. 177, 7346–7354 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Martín-Fontecha, A. et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615–621 (2003). This reference demonstrates that DCs have to express CCR7 to migrate from the skin to peripheral lymph nodes under inflammatory conditions, and reference 13 shows that CCR7 is also indispensable for DC migration in non-inflammatory, steady-state situations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Worbs, T. et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006). This reference and reference 31 show that CCR7-dependent migration of antigen-carrying DCs into the draining lymph nodes is required for the induction of tolerance to ingested and inhaled antigens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Johansson-Lindbom, B. et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jang, M. H. et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Gunn, M. D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marsland, B. J. et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity 22, 493–505 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Yanagawa, Y. & Onoe, K. CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities. Blood 101, 4923–4929 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Worbs, T., Mempel, T. R., Boelter, J., von Andrian, U. H. & Förster, R. CCR7-ligands stimulate the intranodal motility of T lymphocytes in vivo. J. Exp. Med. 204, 489–495 (2007). References 40–42 demonstrate that CCR7 influences the motility of lymphocytes in lymph nodes. In addition, reference 43 shows that, in the absence of shear forces, lymph-node chemokines promote T-cell motility without triggering firm integrin adhesiveness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Okada, T. & Cyster, J. G. CC chemokine receptor 7 contributes to Gi-dependent T cell motility in the lymph node. J. Immunol. 178, 2973–2978 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Huang, J. H. et al. Requirements for T lymphocyte migration in explanted lymph nodes. J. Immunol. 178, 7747–7755 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Woolf, E. et al. Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nature Immunol. 8, 1076–1085 (2007).

    Article  CAS  Google Scholar 

  44. Hardtke, S., Ohl, L. & Förster, R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 106, 1924–1931 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Arnold, C. N., Campbell, D. J., Lipp, M. & Butcher, E. C. The germinal center response is impaired in the absence of T cell-expressed CXCR5. Eur. J. Immunol. 37, 100–109 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Scandella, E. et al. Dendritic cell-independent B cell activation during acute virus infection: a role for early CCR7-driven B–T helper cell collaboration. J. Immunol. 178, 1468–1476 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Junt, T. et al. Antiviral immune responses in the absence of organized lymphoid T cell zones in plt/plt mice. J. Immunol. 168, 6032–6040 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Junt, T. et al. Impact of CCR7 on priming and distribution of antiviral effector and memory CTL. J. Immunol. 173, 6684–6693 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Kursar, M. et al. Differential requirements for the chemokine receptor CCR7 in T cell activation during Listeria monocytogenes infection. J. Exp. Med. 201, 1447–1457 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schneider, M. A., Meingassner, J. G., Lipp, M., Moore, H. D. & Rot, A. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J. Exp. Med. 204, 735–745 (2007). This study, along with reference 59, demonstrates that CCR7 is required for the migration of T Reg cells into lymph nodes and that this homing is essential for the unimpaired function of T Reg cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pahuja, A. et al. Experimental autoimmune encephalomyelitis develops in CC chemokine receptor 7-deficient mice with altered T-cell responses. Scand. J. Immunol. 64, 361–369 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Mori, S. et al. Mice lacking expression of the chemokines CCL21-ser and CCL19 (plt mice) demonstrate delayed but enhanced T cell immune responses. J. Exp. Med. 193, 207–218 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Grinnan, D. et al. Enhanced allergen-induced airway inflammation in paucity of lymph node T cell (plt) mutant mice. J. Allergy Clin. Immunol. 118, 1234–1241 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Saleh, S. et al. CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T-cells to HIV-1 infection: a novel model of HIV-1 latency. Blood 110, 4161–4164 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Pron, B. et al. Dendritic cells are early cellular targets of Listeria monocytogenes after intestinal delivery and are involved in bacterial spread in the host. Cell. Microbiol. 3, 331–340 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Baluk, P. et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med. 204, 2349–2362 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).

    Article  CAS  Google Scholar 

  58. Menning, A. et al. Distinctive role of CCR7 in migration and functional activity of naive- and effector/memory-like Treg subsets. Eur. J. Immunol. 37, 1575–1583 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Kocks, J. R., Davalos-Misslitz, A. C., Hintzen, G., Ohl, L. & Förster, R. Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J. Exp. Med. 204, 723–734 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mueller, S. N. et al. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science 317, 670–674 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nature Immunol. 6, 1219–1227 (2005).

    Article  CAS  Google Scholar 

  62. Liang, S. et al. Conversion of CD4+ CD25-– cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J. Exp. Med. 201, 127–137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mann, M. K., Maresz, K., Shriver, L. P., Tan, Y. & Dittel, B. N. B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J. Immunol. 178, 3447–3456 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Huehn, J. et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J. Exp. Med. 199, 303–313 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lee, J. H., Kang, S. G. & Kim, C. H. FoxP3+ T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues. J. Immunol. 178, 301–311 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Davalos-Misslitz, A. C. et al. Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur. J. Immunol. 37, 613–622 (2007). References 66–68 demonstrate that establishment of central tolerance is impaired in the absence of CCR7 signalling, and that CCR7-deficient mice develop autoimmunity.

    Article  CAS  PubMed  Google Scholar 

  67. Kurobe, H. et al. CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24, 165–177 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Davalos-Misslitz, A. C., Worbs, T., Willenzon, S., Bernhardt, G. & Förster, R. Impaired responsiveness to TCR stimulation and defective negative selection of thymocytes in CCR7-deficient mice. Blood 110, 4351–4359 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Hoepken, U. E. et al. CCR7 deficiency causes ectopic lymphoid neogenesis and disturbed mucosal tissue integrity. Blood 109, 886–895 (2006).

    Article  CAS  Google Scholar 

  70. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nature Rev. Immunol. 6, 205–217 (2006).

    Article  CAS  Google Scholar 

  71. Fan, L., Reilly, C. R., Luo, Y., Dorf, M. E. & Lo, D. Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J. Immunol. 164, 3955–3959 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. Martin, A. P. et al. A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. J. Immunol. 173, 4791–4798 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Chen, S. C. et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J. Immunol. 168, 1001–1008 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Grant, A. J. et al. Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am. J. Pathol. 160, 1445–1455 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Christopherson, K. W., Hood, A. F., Travers, J. B., Ramsey, H. & Hromas, R. A. Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases. Blood 101, 801–806 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Weninger, W. et al. Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis. J. Immunol. 170, 4638–4648 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Marinkovic, T. et al. Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J. Clin. Invest. 116, 2622–2632 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wengner, A. M. et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 56, 3271–3283 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Petrie, H. T. Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nature Rev. Immunol. 3, 859–866 (2003).

    Article  CAS  Google Scholar 

  81. Takahama, Y. Journey through the thymus: stromal guides for T-cell development and selection. Nature Rev. Immunol. 6, 127–135 (2006).

    Article  CAS  Google Scholar 

  82. Bleul, C. C. & Boehm, T. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30, 3371–3379 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Liu, C. et al. The role of CCL21 in recruitment of T-precursor cells to fetal thymi. Blood 105, 31–39 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Ueno, T. et al. CCR7 signals are essential for cortex–medulla migration of developing thymocytes. J. Exp. Med. 200, 493–505 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ueno, T. et al. Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16, 205–218 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Hogquist, K. A., Baldwin, T. A. & Jameson, S. C. Central tolerance: learning self-control in the thymus. Nature Rev. Immunol. 5, 772–782 (2005).

    Article  CAS  Google Scholar 

  87. Baekkevold, E. S. et al. The CCR7 ligand ELC (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J. Exp. Med. 193, 1105–1112 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Warnock, R. A. et al. The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer's patch high endothelial venules. J. Exp. Med. 191, 77–88 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  90. Ohl, L. et al. Cooperating mechanisms of CXCR5 and CCR7 in development and organization of secondary lymphoid organs. J. Exp. Med. 197, 1199–1204 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank T. Worbs and G. Bernhardt for valuable suggestions on this manuscript. A.R. is supported by the EU 6th Framework Program collaborative grant INNOCHEM (LSHB-CT-2005-518167). R.F. is supported by grants from the German Research Foundation (DFG SFB621-A1, DFG SFB587-B3, DFG SFB566-A14, DFG SFB738-B5). We regret that, owing to space limitations, we could not always adequately quote the work of our colleagues contributing to the field reviewed here.

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  1. Institute of Immunology, Hannover Medical School,

    Reinhold Förster & Ana Clara Davalos-Misslitz

  2. 30625, Hannover, Germany

    Reinhold Förster & Ana Clara Davalos-Misslitz

  3. Novartis Institutes for BioMedical Research, Brunnerstrasse 59, Vienna, A-1235, Vienna, Austria

    Antal Rot

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Glossary

Regulatory T (TReg) cell

A naturally occurring subtype of regulatory T cell, which develops in the thymus and regulates self-reactive T cells in the periphery. TReg cells are characterized by the expression of CD25 (interleukin-2 receptor α-chain) and the transcription factor FOXP3 (forkhead box P3).

Paucity of lymph-node T cells (plt/plt) mice

A spontaneously occurring mutant strain that lost the expression of the CC-chemokine receptor 7 (CCR7)-ligands CC-chemokine ligand (CCL19) and the lymphoid tissue form of CCL21 (CCL21-Ser). Lack of these chemokines results in defective thymic architecture and function, as well as impaired migration of CCR7-expressing T cells and dendritic cells into lymphoid organs, leading to their hypocellularity.

Central memory T (TCM) cell

A memory T-cell subpopulation that lacks immediate effector function but that expresses the lymph-node homing molecules L-selectin (CD62L) and CC-chemokine receptor 7 (CCR7). Tcm cells rapidly develop the phenotype and function of effector T cells on antigen re-stimulation in lymphoid organs.

Immunoglobulin class switching

A process in B cells by which the class of a secreted immunoglobulin is changed (for example, from IgM to IgG) without altering its antigen specificity.

Contact hypersensitivity

A form of delayed-type hypersensitivity (type IV), in which T cells respond to antigens that are introduced through skin contact. This step requires dendritic-cell mobilization from the skin to the draining lymph nodes to prime the antigen-specific T cells.

Severe combined immunodeficiency (SCID) mice

Spontaneous mutant mice in which T and B cells are absent. SCID mice lack functional lymphocytes because they have a deficiency that impairs rearrangement of different immunoglobulin and T-cell receptor genes. Lack of T and B cells leads to defects in cell-mediated and humoral immune responses.

Sjögren's syndrome

An autoimmune disorder in which immune cells attack and destroy exocrine glands. The hallmarks of Sjögren's syndrome are dry eyes and dry mouth. The disease is often associated with arthritis.

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Förster, R., Davalos-Misslitz, A. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8, 362–371 (2008). https://doi.org/10.1038/nri2297

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  • DOI: https://doi.org/10.1038/nri2297

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