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Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo

Abstract

The naïve and memory T lymphocyte pools are maintained through poorly understood homeostatic mechanisms that may include signaling via cytokine receptors. We show that interleukin-7 (IL-7) plays multiple roles in regulating homeostasis of CD8+ T cells. We found that IL-7 was required for homeostatic expansion of naïve CD8+ and CD4+ T cells in lymphopenic hosts and for CD8+ T cell survival in normal hosts. In contrast, IL- 7 was not necessary for growth of CD8+ T cells in response to a virus infection but was critical for generating T cell memory. Up-regulation of Bcl-2 in the absence of IL-7 signaling was impaired after activation in vivo. Homeostatic proliferation of memory cells was also partially dependent on IL-7. These results point to IL-7 as a pivotal cytokine in T cell homeostasis.

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Figure 1: IL-7R is regulated during T cell activation and memory induction.
Figure 2: IL-7 drives the homeostatic proliferation of naïve T cells.
Figure 3: IL-7 produced by non-BM–derived cells is important for CD8+ T cell proliferation in a lymphopenic host.
Figure 4: IL-7R is required for CD8+ T cell survival in normal hosts.
Figure 5: IL-7R is dispensable for antigen-induced expansion but is essential for CD8+ memory T cell production.
Figure 6: Re-expression of Bcl-2 is partially impaired in IL-7R–deficient OT-I T cells.
Figure 7: Memory CD8+ OT-I T cells are partially dependent on IL-7 for homeostatic proliferation.

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References

  1. Tanchot, C., Rosado, M. M., Agenes, F., Freitas, A. A. & Rocha, B. Lymphocyte homeostasis. Semin. Immunol. 9, 331–337 (1997).

    Article  CAS  Google Scholar 

  2. Tanchot, C. & Rocha, B. The peripheral T cell repertoire: independent homeostatic regulation of virgin and activated CD8(+) T cell pools Eur. J. Immunol. 25, 2127–2136 (1995).

    Article  CAS  Google Scholar 

  3. Berzins, S. P., Boyd, R. L. & Miller, J. F. The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J. Exp. Med. 187, 1839–1848 (1998).

    Article  CAS  Google Scholar 

  4. Tanchot, C., Lemonnier, F.A., Perarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naïve or memory T cells. Science 276, 2057–2062 (1997).

    Article  CAS  Google Scholar 

  5. Nesic, D. & Vukmanovic, S. MHC class I is required for peripheral accumulation of CD8+ thymic emigrants. J. Immunol. 160, 3705–3712 (1998).

    CAS  PubMed  Google Scholar 

  6. Takeishi, T., Lemonnier, F. A., Perarnau, B., Freitas, A. A. & Rocha, B. MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity 5, 217–228 (1996).

    Article  Google Scholar 

  7. Brocker, T. Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J. Exp. Med. 186, 1223–1232 (1997).

    Article  CAS  Google Scholar 

  8. Bruno, L., Kirberg, J. & von Boehmer, H. On the cellular basis of immunological T cell memory. Immunity 2, 37–43 (1995).

    Article  CAS  Google Scholar 

  9. Bruno, L., von Boehmer, H. & Kirberg, J. Cell division in the compartment of naïve and memory T lymphocytes. Eur. J. Immunol. 26, 3179–3184 (1996).

    Article  CAS  Google Scholar 

  10. Tough, D. F. & Sprent, J. Turnover of naïve- and memory-phenotype T cells. J. Exp. Med. 179, 1127–1135 (1994).

    Article  CAS  Google Scholar 

  11. Bell, E. B., Sparshott, S. M., Drayson, M. T. & Ford, W. L. The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature cells. J. Immunol. 139, 1379–1384 (1987).

    CAS  PubMed  Google Scholar 

  12. Rocha, B., Dautigny, N. & Pereira, P. Peripheral T lymphocytes:expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo. Eur. J. Immunol. 19, 905–911 (1989).

    Article  CAS  Google Scholar 

  13. Goldrath, A. W. & Bevan, M. J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (2000).

    Article  Google Scholar 

  14. Ernst, B., Lee, D. -S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (2000).

    Article  Google Scholar 

  15. Kieper, W. C. & Jameson, S. C. Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands. Proc. Natl Acad. Sci. USA 96, 13306–13311 (2000).

    Article  Google Scholar 

  16. Murali-Krishna, K. et al. Persistence of memory CD8 T cells in MHC class I-deficient mice. Science 286, 1377–1381 (1999).

    Article  CAS  Google Scholar 

  17. Swain, S. L., Hu, H. & Huston, G. Class II-independent generation of CD4 memory T cells from effectors. Science 286, 1381–1383 (1999).

    Article  CAS  Google Scholar 

  18. Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

    Article  CAS  Google Scholar 

  19. Boursalian, T. E. & Bottomly, K. Survival of naïve CD4 T cells: roles of restricting versus selecting MHC class II and cytokine milieu. J. Immunol. 162, 3795–3801 (1999).

    CAS  PubMed  Google Scholar 

  20. Lantz, O., Grandjean, I., Matzinger, P. & Di Santo, J. P. γ chain required for naøve CD4+ T cell survival but not for antigen proliferation. Nature Immunol. 1, 54–58 (2000).

    Article  CAS  Google Scholar 

  21. Marrack, P. et al. Homeostasis of αβ TCR+ T cells. Nature Immunol. 1, 107–111 (2000).

    Article  CAS  Google Scholar 

  22. von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

    Article  CAS  Google Scholar 

  23. Grabstein, K. H. et al. Regulation of T cell proliferation by IL-7. J. Immunol. 144, 3015–3020 (1990).

    CAS  PubMed  Google Scholar 

  24. Maraskovsky, E. et al. Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells. J. Immunol. 157, 5315–5323 (1996).

    CAS  PubMed  Google Scholar 

  25. Hassan, J. & Reen, D. J. IL-7 promotes the survival and maturation but not differentiation of human post-thymic CD4+ T cells. Eur. J. Immunol. 28, 3057–3655 (1998).

    Article  CAS  Google Scholar 

  26. Vella, A. T., Teague, T. K., Ihle, J. N., Kappler, J. & Marrack, P. Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4. J. Exp. Med. 186, 325–330 (1997).

    Article  CAS  Google Scholar 

  27. Kim, S. K., Schluns, K. S. & Lefrançois, L. Induction and visualization of mucosal memory CD8 T cells following systemic virus infection. J. Immunol. 163, 4125–4132 (1999).

    CAS  PubMed  Google Scholar 

  28. Schober, S.L. et al. Expression of the transcription factor Lung Kruppel-Like Factor is regulated by cytokines and correlates with survival of memory T cells in vitro and in vivo. J. Immunol. 163, 3662–3667 (1999).

    CAS  PubMed  Google Scholar 

  29. Levin, S. D. et al. Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. J. Immunol. 162, 677–683 (1999).

    CAS  PubMed  Google Scholar 

  30. Kondo, M. et al. Sharing of the interleukin-2 (IL-2) receptor γ chain between receptors for IL-2 and IL-4. Science 262, 1874–1877 (1993).

    Article  CAS  Google Scholar 

  31. Noguchi, M. et al. Interleukin-2 receptor γ chain: a functional component of the interleukin-7 receptor. Science 262, 1877–1800 (1993).

    Article  CAS  Google Scholar 

  32. Pandey, A. et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nature Immunol. 1, 59–64 (2000).

    Article  CAS  Google Scholar 

  33. Kim, S.K. et al. Generation of mucosal cytotoxic T cells against soluble protein by tissue-specific environmental and costimulatory signals. Proc. Natl Acad. Sci. USA 95, 10814–10819 (1998).

    Article  CAS  Google Scholar 

  34. Gudmundsdottir, H., Wells, A. D. & Turka, L. A. Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: effector function is linked to proliferative capacity. J. Immunol. 162, 5212–5223 (1999).

    CAS  PubMed  Google Scholar 

  35. Limanni, A. et al. Ligand gene expression in normal and sublethally irradiated mice. Blood 85, 2377–2384 (1995).

    CAS  PubMed  Google Scholar 

  36. Peterson, V. M. et al. Gene expression of hematoregulatory cytokines is elevated endogenously after sublethal gamma irradiation and is differentially enhanced by therapeutic administration of biologic response modifiers. J. Immunol. 153, 2321–2330 (1994).

    CAS  PubMed  Google Scholar 

  37. Harrison, D. E. & Russell, E. S. The response of W/Wv and Sl/Sld anaemic mice to haemopoietic stimuli. Br. J. Haematol. 22, 155–168 (1972).

    Article  CAS  Google Scholar 

  38. Hong, J. H. et al. Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation. Int. J. Radiat. Biol. 75, 1421–1427 (1999).

    Article  CAS  Google Scholar 

  39. Moore, N. C., Anderson, G., Smith, C. A., Owen, J. J. T. & Jenkinson, E. J. Analysis of cytokine gene expression in subpopulations of freshly isolated thymocytes and thymic stromal cells using semiquantitative polymerase chain reaction. Eur. J. Immunol. 23, 922–927 (1993).

    Article  CAS  Google Scholar 

  40. Funk, P. E., Stephan, R. P. & Witte, P. L. Vascular cell adhesion molecule 1-positive reticular cells express interleukin-7 and stem cell factor in the bone marrow. Blood 86, 2661–2671 (1995).

    CAS  PubMed  Google Scholar 

  41. Sorg, R. V., Mclellan, A. D., Hock, B. D., Fearnley, D. B. & Hart, D. N. Human dendritic cells express functional interleukin-7. Immunobiol. 198, 514–526 (1998).

    Article  CAS  Google Scholar 

  42. Kroncke, R., Loppnow, H., Flad, H. D. & Gerdes, J. Human follicular dendritic cells and vascular cells produce interleukin-7: a potential role for interleukin-7 in the germinal center reaction. Eur. J. Immunol. 26, 2541–2544 (1996).

    Article  CAS  Google Scholar 

  43. Grayson, J. M., Zajac, A. J. A. & Ahmed, R. Increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).

    Article  CAS  Google Scholar 

  44. von Freeden-Jeffry, U., Solvason, N., Howard, M. & Murray, R. The earliest T lineage-committed cells depend on IL-7 for bcl-2 expression and normal cell cycle progression. Immunity 7, 147–154 (1997).

    Article  CAS  Google Scholar 

  45. Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R. & Weissman, I.L. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89, 1033–1041 (1997).

    Article  CAS  Google Scholar 

  46. Kim, K., Lee, C. K., Sayers, T. J., Muegge, K. & Durum, S. K. The trophic action of IL-7 on pro-T cells: inhibition of apoptosis pro-T1, -T2, and T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. J. Immunol. 160, 5735–5741 (1998).

    CAS  PubMed  Google Scholar 

  47. Moore, T. A., von Freeden-Jeffry, U., Murray, R. & Zlotnik, A. Inhibition of γδ T cell development and early thymocyte maturation in IL-7−/− mice. J. Immunol. 157, 2366–2373 (1996).

    CAS  PubMed  Google Scholar 

  48. Kuo, C. T., Veselits, M. L. & Leiden, J. M. LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science 277, 1986–900 (1997).

    Article  CAS  Google Scholar 

  49. Zhang, X., Sun, S., Hwang, I., Tough, D. F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591–599 (1998).

    Article  CAS  Google Scholar 

  50. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).

    Article  CAS  Google Scholar 

  51. Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in Interleukin-15-deficient mice. J. Exp. Med. 191, 771–780 (2000).

    Article  CAS  Google Scholar 

  52. Watanabe, M. et al. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J. Clin. Invest. 95, 2945–2953 (1995).

    Article  CAS  Google Scholar 

  53. Wiles, M. V., Ruiz, P. & Imhof, B. A. Interleukin-7 expression during mouse thymus development. Eur. J. Immunol. 22, 1037–1042 (1992).

    Article  CAS  Google Scholar 

  54. Bender, J. R., Mitchell, T., Kappler, J. & Marrack, P. CD4+ T cell division in irradiated mice requires peptides distinct from those responsible for thymic selection. J. Exp. Med. 190, 367–374 (1999).

    Article  CAS  Google Scholar 

  55. Ariel, A. et al. Induction of T cell adhesion to extracellular matrix or endothelial cell ligands by soluble or matrix-bound interleukin-7. Eur. J. Immunol. 27, 2562–2570 (1997).

    Article  CAS  Google Scholar 

  56. Peschon, J. J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    Article  CAS  Google Scholar 

  57. Hogquist, K. A. et al. T cell receptor antagonistic peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  58. Sarmiento, M., Glasebrook, A. L. & Fitch, F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt-2 antigen block T cell-mediated cytolysis in the absence of complement. J. Immunol. 125, 2665–2672 (1980).

    CAS  PubMed  Google Scholar 

  59. Shen, F. W. in Monoclonal Antibodies and T-cell Hybridomas. Perspectives and technical advances (eds Hammerling, G. J., Hammerling, U. & Kearney, J. F.) 25–31 (Elsevier/North-Holland Inc., Amsterdam, 1981).

    Google Scholar 

  60. Suda, T. et al. Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc. Natl Acad. Sci. USA 90, 9125–9129 (1993).

    Article  Google Scholar 

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Acknowledgements

Supported by NIH grants AI35917 and DK45260 (to L. L), AI38903 and ACS RPG-99-264 (to S. C. J.), and NIH training grant AR-07582 (to K. S.) and NIH training grant AI-07313 (to W. C. K.).

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Correspondence to Leo Lefrançois.

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Schluns, K., Kieper, W., Jameson, S. et al. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol 1, 426–432 (2000). https://doi.org/10.1038/80868

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