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Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells

Nature Immunology volume 8, pages 1255–1265 (2007)Cite this article

Abstract

Interleukin 7 is essential for the survival of naive T lymphocytes. Despite its importance, its cellular source in the periphery remains poorly defined. Here we report a critical function for lymph node access in T cell homeostasis and identify T zone fibroblastic reticular cells in these organs as the main source of interleukin 7. In vitro, T zone fibroblastic reticular cells were able to prevent the death of naive T lymphocytes but not of B lymphocytes by secreting interleukin 7 and the CCR7 ligand CCL19. Using gene-targeted mice, we demonstrate a nonredundant function for CCL19 in T cell homeostasis. Our data suggest that lymph nodes and T zone fibroblastic reticular cells have a key function in naive CD4+ and CD8+ T cell homeostasis by providing a limited reservoir of survival factors.

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Figure 1: Access to SLOs is important for maintenance of the peripheral T cell pool.
Figure 2: IL-7 is produced mainly in the T zone of SLOs.
Figure 3: The gp38+CD31− FRCs are the main source of IL-7 in naive lymph nodes.
Figure 4: TRCs are myofibroblasts enwrapping conduits.
Figure 5: TRCs support the survival of naive T cells in vitro.
Figure 6: In vitro, stromal cells mediate T cell survival by means of IL-7 and CCL19.
Figure 7: Structure of PLNs and homing of T cells and B cells into SLOs is normal in adult CCL19-deficient mice.
Figure 8: CCL19 is involved in naive T cell homeostasis in vivo.

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References

  1. Marrack, P. & Kappler, J. Control of T cell viability. Annu. Rev. Immunol. 22, 765–787 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Surh, C.D. & Sprent, J. Regulation of mature T cell homeostasis. Semin. Immunol. 17, 183–191 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Freitas, A.A. & Rocha, B. Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol. 18, 83–111 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Jiang, Q. et al. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev. 16, 513–533 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Trinder, P.K. & Maeurer, M.J. in The Cytokine Handbook (eds. Thomson, A.W. & Lotze, M.T.) 305–345 (Elsevier Science, London, 2003).

    Book  Google Scholar 

  6. Ma, A., Koka, R. & Burkett, P. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu. Rev. Immunol. 24, 657–679 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Cinalli, R.M. et al. T cell homeostasis requires G protein-coupled receptor-mediated access to trophic signals that promote growth and inhibit chemotaxis. Eur. J. Immunol. 35, 786–795 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dai, Z. & Lakkis, F.G. Cutting edge: Secondary lymphoid organs are essential for maintaining the CD4, but not CD8, naive T cell pool. J. Immunol. 167, 6711–6715 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Dummer, W., Ernst, B., LeRoy, E., Lee, D. & Surh, C. Autologous regulation of naive T cell homeostasis within the T cell compartment. J. Immunol. 166, 2460–2468 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. von Andrian, U.H. & Mempel, T.R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. 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 

  13. Gretz, J.E., Anderson, A.O. & Shaw, S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156, 11–24 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Lepault, F., Gagnerault, M.C., Faveeuw, C. & Boitard, C. Recirculation, phenotype and functions of lymphocytes in mice treated with monoclonal antibody MEL-14. Eur. J. Immunol. 24, 3106–3112 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Lo, C.G., Xu, Y., Proia, R.L. & Cyster, J.G. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 201, 291–301 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lo, C.G., Lu, T.T. & Cyster, J.G. Integrin-dependence of lymphocyte entry into the splenic white pulp. J. Exp. Med. 197, 353–361 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Berlin-Rufenach, C. et al. Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice. J. Exp. Med. 189, 1467–1478 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakano, H. et al. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. Blood 91, 2886–2895 (1998).

    CAS  PubMed  Google Scholar 

  21. 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 

  22. Farr, A.G. et al. Characterization and cloning of a novel glycoprotein expressed by stromal cells in T-dependent areas of peripheral lymphoid tissues. J. Exp. Med. 176, 1477–1482 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Kriehuber, E. et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp. Med. 194, 797–808 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Honda, K. et al. Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis. J. Exp. Med. 193, 621–630 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Ngo, V.N. et al. Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189, 403–412 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bergers, G. & Song, S. The role of pericytes in blood-vessel formation and maintenance. Neuro. Oncol. 7, 452–464 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mazzucchelli, R. & Durum, S.K. Interleukin-7 receptor expression: intelligent design. Nat. Rev. Immunol. 7, 144–154 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Hinz, B. & Gabbiani, G. Mechanisms of force generation and transmission by myofibroblasts. Curr. Opin. Biotechnol. 14, 538–546 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Gabbiani, G. The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 200, 500–503 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Hinz, B., Celetta, G., Tomasek, J.J., Gabbiani, G. & Chaponnier, C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sanchez-Sanchez, N. et al. Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood 104, 619–625 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Endharti, A.T., Zhou, Y.W., Nakashima, I. & Suzuki, H. Galectin-1 supports survival of naive T cells without promoting cell proliferation. Eur. J. Immunol. 35, 86–97 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Kimura, K. et al. Role of glycosaminoglycans in the regulation of T cell proliferation induced by thymic stroma-derived T cell growth factor. J. Immunol. 146, 2618–2624 (1991).

    CAS  PubMed  Google Scholar 

  36. 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 

  37. Mackay, F. & Ambrose, C. The TNF family members BAFF and APRIL: the growing complexity. Cytokine Growth Factor Rev. 14, 311–324 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Schluns, K.S., Kieper, W.C., Jameson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Zhou, Y.W. et al. Murine lymph node-derived stromal cells effectively support survival but induce no activation/proliferation of peripheral resting T cells in vitro. Immunology 109, 496–503 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Feuillet, V., Lucas, B., Di Santo, J.P., Bismuth, G. & Trautmann, A. Multiple survival signals are delivered by dendritic cells to naive CD4+ T cells. Eur. J. Immunol. 35, 2563–2572 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Hara, T. et al. A transmembrane chemokine, CXC chemokine ligand 16, expressed by lymph node fibroblastic reticular cells has the potential to regulate T cell migration and adhesion. Int. Immunol. 18, 301–311 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Ploix, C., Lo, D. & Carson, M.J. A ligand for the chemokine receptor CCR7 can influence the homeostatic proliferation of CD4 T cells and progression of autoimmunity. J. Immunol. 167, 6724–6730 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, J.W., Ferris, R.L. & Whiteside, T.L. Chemokine C receptor 7 expression and protection of circulating CD8+ T lymphocytes from apoptosis. Clin. Cancer Res. 11, 7901–7910 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Sanchez-Sanchez, N., Riol-Blanco, L. & Rodriguez-Fernandez, J.L. The multiple personalities of the chemokine receptor CCR7 in dendritic cells. J. Immunol. 176, 5153–5159 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. 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 

  48. Worbs, T., Mempel, T.R., Bolter, J., von Andrian, U.H. & Forster, R. CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J. Exp. Med. 204, 489–495 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zamisch, M. et al. Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J. Immunol. 174, 60–67 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Goffin, J.M. et al. Focal adhesion size controls tension-dependent recruitment of α-smooth muscle actin to stress fibers. J. Cell Biol. 172, 259–268 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Ansel, S. Bell, M. Charmoy, T. Andresen, P. Hyman, N. Killeen and J. Smith-Clerc for technical help; H. Robson MacDonald for critical reading of the manuscript; M. Cooper, W. van Ewijk, A. Farr, G. Gabbiani, B. Imhof, C. Ruegg and A. Wilson for antibodies; and N. Killeen for embryonic stem cells. Supported by the Swiss National Science Foundation (PPOOA-68805 to S.A.L.), the Boehringer Ingelheim Fonds (T.K.V.), the Swiss National Science Foundation (3100A0-102150/1 and 3100A0-113733/1 to B.H.) and the National Institutes of Health (AI45073 to J.G.C.).

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  1. Alexander Link and Tobias K Vogt: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, University of Lausanne, Epalinges, 1066, Switzerland

    Alexander Link, Tobias K Vogt, Stéphanie Favre, Mirjam R Britschgi, Hans Acha-Orbea & Sanjiv A Luther

  2. Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, 1015, Switzerland

    Boris Hinz

  3. Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, 94143-0414, California, USA

    Jason G Cyster

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Contributions

A.L. did the in vivo experiments, with assistance from M.R.B. and S.F., as well as all the in vitro assays, flow cytometry sorting and analysis, and in situ hybridization, and contributed to the writing of the manuscript; T.K.V. did the wrinkling assays in collaboration with B.H. and did the RT-PCR and assisted with the flow cytometry sorting and analysis; S.F. did most of the immunofluorescence with assistance from T.K.V.; H.A.-O. provided antibodies; S.A.L. generated the CCL19-deficient mice in the laboratory of J.G.C.; S.A.L. directed the study and wrote the manuscript; and all authors critically reviewed the manuscript.

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Correspondence to Sanjiv A Luther.

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Link, A., Vogt, T., Favre, S. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol 8, 1255–1265 (2007). https://doi.org/10.1038/ni1513

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