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L-selectin-negative CCR7− effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells

Nature Immunology volume 8, pages 743–752 (2007)Cite this article

Abstract

T lymphocytes lacking the lymph node–homing receptors L-selectin and CCR7 do not migrate to lymph nodes in the steady state. Instead, we found here that lymph nodes draining sites of mature dendritic cells or adjuvant inoculation recruited L-selectin-negative CCR7− effector and memory CD8+ T cells. This recruitment required CXCR3 expression on T cells and occurred through high endothelial venules in concert with lumenal expression of the CXCR3 ligand CXCL9. In reactive lymph nodes, recruited T cells established stable interactions with and killed antigen-bearing dendritic cells, limiting the ability of these dendritic cells to activate naive CD4+ and CD8+ T cells. The inducible recruitment of blood-borne effector and memory T cells to lymph nodes may represent a mechanism for terminating primary and limiting secondary immune responses.

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Figure 1: In vitro–generated L-selectin-negative CCR7− effector CD8+ T cells are excluded from resting lymph nodes but migrate to reactive lymph nodes.
Figure 2: Effector and effector memory CD8+ T cells generated by in vivo priming rapidly migrate to reactive lymph nodes.
Figure 3: Effector T cells roll and stick on HEVs of reactive lymph nodes.
Figure 4: CXCR3 is required for the migration of effector CD8+ T cells to reactive lymph nodes.
Figure 5: CXCL9 is transiently displayed on the lumenal surfaces of HEVs in reactive lymph nodes.
Figure 6: Effector and memory CD8+ T cells kill antigen-presenting DCs in reactive lymph nodes.
Figure 7: Priming of naive CD4+ and CD8+ T cells is inhibited in mice containing effector or memory CD8+ T cells.

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References

  1. Sallusto, F., Mackay, C.R. & Lanzavecchia, A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu. Rev. Immunol. 18, 593–620 (2000).

    Article  CAS  Google Scholar 

  2. Springer, T.A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301–314 (1994).

    Article  CAS  Google Scholar 

  3. Butcher, E.C. & Picker, L.J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Lindquist, R.L. et al. Visualizing dendritic cell networks in vivo . Nat. Immunol. 5, 1243–1250 (2004).

    Article  CAS  Google Scholar 

  7. Mempel, T.R., Henrickson, S.E. & Von Andrian, U.H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004).

    Article  CAS  Google Scholar 

  8. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    Article  CAS  Google Scholar 

  9. Austrup, F. et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 385, 81–83 (1997).

    Article  CAS  Google Scholar 

  10. Roman, E. et al. CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function. J. Exp. Med. 196, 957–968 (2002).

    Article  CAS  Google Scholar 

  11. Yoneyama, H. et al. Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes. J. Exp. Med. 195, 1257–1266 (2002).

    Article  CAS  Google Scholar 

  12. Lawrence, C.W. & Braciale, T.J. Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection. J. Immunol. 173, 1209–1218 (2004).

    Article  CAS  Google Scholar 

  13. Sallusto, F., Lenig, D., Forster, 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  Google Scholar 

  14. Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).

    Article  CAS  Google Scholar 

  15. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

    Article  CAS  Google Scholar 

  16. Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).

    Article  CAS  Google Scholar 

  17. Ferlazzo, G. et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J. Exp. Med. 195, 343–351 (2002).

    Article  CAS  Google Scholar 

  18. Yang, J., Huck, S.P., McHugh, R.S., Hermans, I.F. & Ronchese, F. Perforin-dependent elimination of dendritic cells regulates the expansion of antigen-specific CD8+ T cells in vivo . Proc. Natl. Acad. Sci. USA 103, 147–152 (2006).

    Article  CAS  Google Scholar 

  19. Chen, Q. et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat. Immunol. 7, 1299–1308 (2006).

    Article  CAS  Google Scholar 

  20. Martin-Fontecha, A. et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5, 1260–1265 (2004).

    Article  CAS  Google Scholar 

  21. Bajenoff, M. et al. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. J. Exp. Med. 203, 619–631 (2006).

    Article  CAS  Google Scholar 

  22. Yoneyama, H. et al. Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. Int. Immunol. 16, 915–928 (2004).

    Article  CAS  Google Scholar 

  23. Hadida, F. et al. Carboxyl-terminal and central regions of human immunodeficiency virus-1 NEF recognized by cytotoxic T lymphocytes from lymphoid organs. An in vitro limiting dilution analysis. J. Clin. Invest. 89, 53–60 (1992).

    Article  CAS  Google Scholar 

  24. Hosmalin, A. et al. HIV-specific effector cytotoxic T lymphocytes and HIV-producing cells colocalize in white pulps and germinal centers from infected patients. Blood 97, 2695–2701 (2001).

    Article  CAS  Google Scholar 

  25. Kyburz, D., Speiser, D.E., Aebischer, T., Hengartner, H. & Zinkernagel, R.M. Virus-specific cytotoxic T cell-mediated lysis of lymphocytes in vitro and in vivo . J. Immunol. 150, 5051–5058 (1993).

    CAS  PubMed  Google Scholar 

  26. Odermatt, B., Eppler, M., Leist, T.P., Hengartner, H. & Zinkernagel, R.M. Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure. Proc. Natl. Acad. Sci. USA 88, 8252–8256 (1991).

    Article  CAS  Google Scholar 

  27. Borrow, P., Evans, C.F. & Oldstone, M.B. Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression. J. Virol. 69, 1059–1070 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Galkina, E. et al. Preferential migration of effector CD8+ T cells into the interstitium of the normal lung. J. Clin. Invest. 115, 3473–3483 (2005).

    Article  CAS  Google Scholar 

  29. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo . J. Exp. Med. 194, 769–779 (2001).

    Article  CAS  Google Scholar 

  30. Gett, A.V., Sallusto, F., Lanzavecchia, A. & Geginat, J. T cell fitness determined by signal strength. Nat. Immunol. 4, 355–360 (2003).

    Article  CAS  Google Scholar 

  31. Mackay, C.R., Marston, W.L. & Dudler, L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171, 801–817 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Martin-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).

    Article  CAS  Google Scholar 

  35. 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  Google Scholar 

  36. Palframan, R.T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).

    Article  CAS  Google Scholar 

  37. von Andrian, U.H., Hasslen, S.R., Nelson, R.D., Erlandsen, S.L. & Butcher, E.C. A central role for microvillous receptor presentation in leukocyte adhesion under flow. Cell 82, 989–999 (1995).

    Article  CAS  Google Scholar 

  38. Stein, J.V. et al. L-selectin-mediated leukocyte adhesion in vivo: microvillous distribution determines tethering efficiency, but not rolling velocity. J. Exp. Med. 189, 37–50 (1999).

    Article  CAS  Google Scholar 

  39. Ronchese, F. & Hermans, I.F. Killing of dendritic cells: a life cut short or a purposeful death? J. Exp. Med. 194, F23–F26 (2001).

    Article  CAS  Google Scholar 

  40. Wilson, J.L. et al. Targeting of human dendritic cells by autologous NK cells. J. Immunol. 163, 6365–6370 (1999).

    CAS  PubMed  Google Scholar 

  41. Medema, J.P. et al. Expression of the serpin serine protease inhibitor 6 protects dendritic cells from cytotoxic T lymphocyte-induced apoptosis: differential modulation by T helper type 1 and type 2 cells. J. Exp. Med. 194, 657–667 (2001).

    Article  CAS  Google Scholar 

  42. Hermans, I.F., Ritchie, D.S., Yang, J., Roberts, J.M. & Ronchese, F. CD8+ T cell-dependent elimination of dendritic cells in vivo limits the induction of antitumor immunity. J. Immunol. 164, 3095–3101 (2000).

    Article  CAS  Google Scholar 

  43. Matloubian, M. et al. A role for perforin in downregulating T-cell responses during chronic viral infection. J. Virol. 73, 2527–2536 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Badovinac, V.P. & Harty, J.T. Adaptive immunity and enhanced CD8+ T cell response to Listeria monocytogenes in the absence of perforin and IFN-γ. J. Immunol. 164, 6444–6452 (2000).

    Article  CAS  Google Scholar 

  45. Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).

    Article  CAS  Google Scholar 

  46. Klenerman, P. & Zinkernagel, R.M. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394, 482–485 (1998).

    Article  CAS  Google Scholar 

  47. Traunecker, A., Oliveri, F. & Karjalainen, K. Myeloma based expression system for production of large mammalian proteins. Trends Biotechnol. 9, 109–113 (1991).

    Article  CAS  Google Scholar 

  48. Clarke, S.R. et al. Characterization of the ovalbumin-specific TCR transgenic line OT-I: MHC elements for positive and negative selection. Immunol. Cell Biol. 78, 110–117 (2000).

    Article  CAS  Google Scholar 

  49. Barnden, M.J., Allison, J., Heath, W.R. & Carbone, F.R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    Article  CAS  Google Scholar 

  50. Hancock, W.W. et al. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J. Exp. Med. 192, 1515–1520 (2000).

    Article  CAS  Google Scholar 

  51. Pope, C. et al. Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection. J. Immunol. 166, 3402–3409 (2001).

    Article  CAS  Google Scholar 

  52. von Andrian, U.H. Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirculation 3, 287–300 (1996).

    Article  CAS  Google Scholar 

  53. Nombela-Arrieta, C. et al. Differential requirements for DOCK2 and phosphoinositide-3-kinase γ during T and B lymphocyte homing. Immunity 21, 429–441 (2004).

    Article  CAS  Google Scholar 

  54. Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440, 890–895 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L. Lefrancois (University of Connecticut) for the Listeria monocytogenes strain expressing OVA; P. Dellabona (DIBIT San Raffaele Research Institute), C. Gerard (Harvard Medical School), J. Kirberg (Max Planck Institute) and M. Lipp (Max Delbruck Center) for transgenic and knockout mice; M. Manz and M. Uguccioni for critical reading and comments; A. Almeida for discussions; and D. Jarrossay, E. Mira-Catò, L. Perlini and M. Convert for technical help. Supported by the Swiss National Science Foundation (31-101962 and 31-109832), the European Commission FP6 'Network of Excellence' initiative (N. LSHG-CT-2003-502935 MAIN, LSHB-CT-2004-512074 DC-THERA and LSHG-CT-2005-005203 MUGEN), the intramural program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Cancer Research Institute (A.H.) and the Helmut Horten Foundation (for the Institute for Research in Biomedicine).

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  1. Alex Y Huang

    Present address: Present address: Division of Pediatric Hematology/Oncology, Rainbow Babies & Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.,

Authors and Affiliations

  1. Institute for Research in Biomedicine, Bellinzona, CH-6500, Switzerland

    Greta Guarda, Miroslav Hons, Alfonso Martín-Fontecha, Antonio Lanzavecchia & Federica Sallusto

  2. Theodor Kocher Institute, University of Bern, Bern, CH-3012, Switzerland

    Silvia F Soriano & Jens V Stein

  3. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Alex Y Huang, Rosalind Polley & Ronald N Germain

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Supplementary information

Supplementary Fig. 1

Priming of naive CD4+ T cells is partially recovered in mice carrying effector or memory CD8+ T cells when MHC class I and class II peptides are provided on different DCs. (PDF 50 kb)

Supplementary Video 1

Dynamic intravital 2-photon imaging movies of prolonged T cell-DC interaction followed by DC cell body fragmentation. SIINFEKL pulsed-DCs (green) and control peptide pulsed-DCs (purple) were activated with LPS and co-injected in the footpad of recipient mice 24 hours prior to intravenous injection of in vitro-generated L-selectin− effector OT-I cells (red). Intravital 2-photon microscopy imaging was performed on the draining popliteal lymph node of anesthetized recipient animals in the interfollicular region 60-160 μm below the capsule starting at 3 hours after adoptive transfer of T cells. An example of prolonged T cell interaction with SIINFEKL pulsed-DCs is shown (highlighted by dotted circle). These prolonged interactions are followed by fragmentation of the DC cell body over the subsequent several minutes. Control peptide pulsed-DCs (purple) are either ignored by or exhibit transient interaction with T cells, and did not exhibit any fragmentation during the same observation period. Clock (h:min:sec) denotes the time after i.v. OT-I cell transfer. Scale bar as indicated. Playback speed: 450X. Total time: 3 hrs 18 mins. (AVI 7938 kb)

Supplementary Video 2

Dynamic intravital 2-photon imaging movies of prolonged T cell-DC interaction followed by DC cell body fragmentation. SIINFEKL pulsed-DCs (green) and control peptide pulsed-DCs (purple) were activated with LPS and co-injected in the footpad of recipient mice 24 hours prior to intravenous injection of in vitro-generated L-selectin− effector OT-I cells (red). Intravital 2-photon microscopy imaging was performed on the draining popliteal lymph node of anesthetized recipient animals in the interfollicular region 60-160 μm below the capsule starting at 3 hours after adoptive transfer of T cells. Shown is an example of prolonged T cell interaction with SIINFEKL pulsed-DCs followed by fragmentation of the DC cell body. Clock (h:min:sec) denotes the time after i.v. OT-I cell transfer. Scale bar as indicated. Playback speed: 450X. Total time: 1 hr 8 mins 45 secs (Movie 2). (AVI 1206 kb)

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Guarda, G., Hons, M., Soriano, S. et al. L-selectin-negative CCR7− effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells. Nat Immunol 8, 743–752 (2007). https://doi.org/10.1038/ni1469

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