Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells

Nature Immunology volume 4, pages 1191–1198 (2003)Cite this article

Abstract

A major unanswered question is what distinguishes the majority of activated CD8 T cells that die after an acute viral infection from the small fraction (5–10%) that survive to become long-lived memory cells. In this study we show that increased expression of the interleukin 7 receptor α-chain (IL-7Rα) identifies the effector CD8 T cells that will differentiate into memory cells. IL-7Rhi effector cells contained increased amounts of antiapoptotic molecules, and adoptive transfer of IL-7Rhi and IL-7Rlo effector cells showed that IL-7Rhi cells preferentially gave rise to memory cells that could persist and confer protective immunity. Thus, selective expression of IL-7R identifies memory cell precursors, and this marker may be useful in predicting the number of memory T cells generated after infection or immunization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased expression of IL-7R directly correlates with effector CD8 T cell survival.
Figure 2: Increased IL-7R expression in effector cells correlates with increased survival signals and less apoptosis.
Figure 3: IL-7Rhi memory cell precursors provide immunological protection.
Figure 4: IL-7Rhi effector cells develop into long-lived memory cells.
Figure 5: Functional requirement of IL-7R expression in memory cell precursor survival.

Similar content being viewed by others

References

  1. Kaech, S.M., Wherry, E.J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251–262 (2002).

    Article  CAS  Google Scholar 

  2. Busch, D.H., Pilip, I.M., Vijh, S. & Pamer, E.G. Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 8, 353–362 (1998).

    Article  CAS  Google Scholar 

  3. Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).

    Article  CAS  Google Scholar 

  4. Kaech, S.M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002).

    Article  CAS  Google Scholar 

  5. Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  6. Becker, T.C. et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195, 1541–1548 (2002).

    Article  CAS  Google Scholar 

  7. 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 

  8. Goldrath, A.W. et al. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).

    Article  CAS  Google Scholar 

  9. Grayson, J.M., Zajac, A.J., Altman, J.D. & Ahmed, R. Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).

    Article  CAS  Google Scholar 

  10. Kieper, W.C. et al. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J. Exp. Med. 195, 1533–1539 (2002).

    Article  CAS  Google Scholar 

  11. 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 

  12. Schluns, K.S., Williams, K., Ma, A., Zheng, X.X. & Lefrancois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002).

    Article  CAS  Google Scholar 

  13. Tan, J.T. et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002).

    Article  CAS  Google Scholar 

  14. 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 

  15. 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 

  16. Rathmell, J.C., Farkash, E.A., Gao, W. & Thompson, C.B. IL-7 enhances the survival and maintains the size of naive T cells. J. Immunol. 167, 6869–6876 (2001).

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Tan, J.T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA 98, 8732–8737 (2001).

    Article  CAS  Google Scholar 

  20. Vella, A., Teague, T.K., Ihle, J., 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 

  21. 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 

  22. Harrington, L.E., Galvan, M., Baum, L.G., Altman, J.D. & Ahmed, R. Differentiating between memory and effector CD8 T cells by altered expression of cell surface O-glycans. J. Exp. Med. 191, 1241–1246 (2000).

    Article  CAS  Google Scholar 

  23. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).

    Article  CAS  Google Scholar 

  24. Voehringer, D. et al. Viral infections induce abundant numbers of senescent CD8 T cells. J. Immunol. 167, 4838–4843 (2001).

    Article  CAS  Google Scholar 

  25. Boothby, M., Mora, A.L. & Stephenson, L.M. Lymphokine-dependent proliferation of T-lymphoid cells: regulated responsiveness and role in vivo. Crit. Rev. Immunol. 21, 487–522 (2001).

    Article  CAS  Google Scholar 

  26. Rathmell, J.C. & Thompson, C.B. Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109, S97–107 (2002).

    Article  CAS  Google Scholar 

  27. van Engeland, M., Nieland, L.J., Ramaekers, F.C., Schutte, B. & Reutelingsperger, C.P. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31, 1–9 (1998).

    Article  CAS  Google Scholar 

  28. Wang, X.Z. et al. Virus-specific CD8 T cells in peripheral tissues are more resistant to apoptosis than those in lymphoid organs. Immunity 18, 631–642 (2003).

    Article  CAS  Google Scholar 

  29. Schluns, K.S. & Lefrancois, L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).

    Article  CAS  Google Scholar 

  30. Prlic, M., Lefrancois, L. & Jameson, S.C. Multiple choices: regulation of memory CD8 T cell generation and homeostasis by interleukin (IL)-7 and IL-15. J. Exp. Med. 195, F49–52 (2002).

    Article  CAS  Google Scholar 

  31. Jameson, S.C. Maintaining the norm: T-cell homeostasis. Nat. Rev. Immunol. 2, 547–556 (2002).

    Article  CAS  Google Scholar 

  32. Van Parijs, L. & Abbas, A.K. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280, 243–248 (1998).

    Article  CAS  Google Scholar 

  33. Plas, D.R., Rathmell, J.C. & Thompson, C.B. Homeostatic control of lymphocyte survival: potential origins and implications. Nat. Immunol. 3, 515–521 (2002).

    Article  CAS  Google Scholar 

  34. Vander Heiden, M.G. et al. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol. Cell. Bio. 21, 5899–5912 (2001).

    Article  CAS  Google Scholar 

  35. Petschner, F. et al. Constitutive expression of Bcl-xL or Bcl-2 prevents peptide antigen-induced T cell deletion but does not influence T cell homeostasis after a viral infection. Eur. J. Immunol. 28, 560–569 (1998).

    Article  CAS  Google Scholar 

  36. Razvi, E.S., Jiang, Z., Woda, B.A. & Welsh, R.M. Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice. Am. J. Path. 147, 79–91 (1995).

    CAS  PubMed  Google Scholar 

  37. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  Google Scholar 

  38. Appay, V. et al. Memory CD8 T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8, 379–385 (2002).

    Article  CAS  Google Scholar 

  39. van Leeuwen, E.M. et al. Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+ T cells. J. Immunol. 169, 5838–5843 (2002).

    Article  CAS  Google Scholar 

  40. Foxwell, B.M., Taylor-Fishwick, D.A., Simon, J.L., Page, T.H. & Londei, M. Activation induced changes in expression and structure of the IL-7 receptor on human T cells. Int. Immunol. 4, 277–282 (1992).

    Article  CAS  Google Scholar 

  41. Xue, H.H. et al. IL-2 negatively regulates IL-7 receptor a chain expression in activated T lymphocytes. Proc. Natl. Acad. Sci. USA 99, 13759–13764 (2002).

    Article  CAS  Google Scholar 

  42. Badovinac, V.P., Tvinnereim, A.R. & Harty, J.T. Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-g. Science 290, 1354–1358 (2000).

    Article  CAS  Google Scholar 

  43. Opferman, J.T., Ober, B.T., Narayanan, R. & Ashton-Rickardt, P.G. Suicide induced by cytolytic activity controls the differentiation of memory CD8+ T lymphocytes. Int. Immunol. 13, 411–419 (2001).

    Article  CAS  Google Scholar 

  44. Murali-Krishna, K. & Ahmed, R. Cutting edge: naive T cells masquerading as memory cells. J. Immunol. 165, 1733–1737 (2000).

    Article  CAS  Google Scholar 

  45. Whitmire, J.K., Murali-Krishna, K., Altman, J. & Ahmed, R. Antiviral CD4 and CD8 T-cell memory: differences in the size of the response and activation requirements. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 355, 373–379 (2000).

    Article  CAS  Google Scholar 

  46. Homann, D., Teyton, L. & Oldstone, M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat. Med. 7, 913–919 (2001).

    Article  CAS  Google Scholar 

  47. Kaech, S.M. & Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat. Immunol. 2, 415–422 (2001).

    Article  CAS  Google Scholar 

  48. Ahmed, R., Jamieson, B.D. & Porter, D.D. Immune therapy of a persistent and disseminated viral infection. J. Virol. 61, 3920–3929 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R. Karaffa for expertise in flow cytometry; Y. Blinder for technical support; and D. Masopust, T. Becker, T. Onami and G. Shadel for discussions. Supported by grants from the National Institutes of Health (to R.A. and C.D.S.), the Damon Runyon-Walter Winchell Cancer Research Fund and Burroughs Wellcome Fund (to S.M.K.), the American Cancer Society (J.T.T.) and the Cancer Research Institute (to E.J.W.), and by the Leukemia and Lymphoma Society (C.D.S.).

Author information

Authors and Affiliations

  1. Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    Susan M Kaech, E John Wherry, Bogumila T Konieczny & Rafi Ahmed

  2. Department of Immunology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Joyce T Tan & Charles D Surh

Authors
  1. Susan M Kaech
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joyce T Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E John Wherry
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bogumila T Konieczny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles D Surh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rafi Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafi Ahmed.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaech, S., Tan, J., Wherry, E. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4, 1191–1198 (2003). https://doi.org/10.1038/ni1009

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1009

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing