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.

  • Letter
  • Published:

Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells

Nature volume 441, pages 890–893 (2006)Cite this article

Abstract

Although interleukin-2 (IL-2) was initially characterized as the primary T-cell growth factor following in vitro activation1, less is known about its role in shaping T-cell responses to acute infections in vivo. The use of IL-2- or IL-2-receptor-deficient mice is problematic owing to their early development of autoimmunity2,3,4,5, attributable to the central role of IL-2 in the generation, maintenance and function of CD4+CD25+ regulatory T cells6,7,8,9. To bypass these inherent difficulties, we have studied the effect of IL-2 on T-cell responses to acute infections by adopting a mixed chimaera strategy in which T cells lacking the high-affinity IL-2 receptor could be studied in an otherwise healthy mouse containing a full complement of regulatory T cells. Here we show that although IL-2 signalling to pathogen-specific CD8+ T cells affects the number of developing effector and memory cells very little, it is required for the generation of robust secondary responses. This is not due to an altered T-cell-receptor repertoire development or selection, and does not reflect an acute requirement for IL-2 during secondary activation and expansion. Rather, we demonstrate a previously unappreciated role for IL-2 during primary infection in programming the development of CD8+ memory T cells capable of full secondary expansion. These results have important implications for the development of vaccination or immunotherapeutic strategies aimed at boosting memory T-cell function.

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: IL-2Rα-deficient CD8 + T cells generate robust primary but defective secondary responses.
Figure 2: IL-2Rα-deficient memory cells are maintained at normal levels.
Figure 3: IL-2Rα-deficient memory cells proliferate but do not accumulate following rechallenge.
Figure 4: IL-2 signalling during the primary response promotes secondary CD8 + T cell responsiveness.

Similar content being viewed by others

References

  1. Smith, K. A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988)

    Article  ADS  CAS  Google Scholar 

  2. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993)

    Article  CAS  Google Scholar 

  3. Schorle, H., Holtschke, T., Hunig, T., Schimpl, A. & Horak, I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621–624 (1991)

    Article  ADS  CAS  Google Scholar 

  4. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995)

    Article  ADS  CAS  Google Scholar 

  5. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995)

    Article  CAS  Google Scholar 

  6. D'Cruz, L. M. & Klein, L. Development and function of agonist-induced CD25+ Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nature Immunol. 6, 1152–1159 (2005)

    Article  CAS  Google Scholar 

  7. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005)

    Article  CAS  Google Scholar 

  8. Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nature Rev. Immunol. 4, 665–674 (2004)

    Article  CAS  Google Scholar 

  9. Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3(+ ) CD25(+ ) CD4(+ ) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005)

    Article  CAS  Google Scholar 

  10. Jameson, S. C. T cell homeostasis: keeping useful T cells alive and live T cells useful. Semin. Immunol. 17, 231–237 (2005)

    Article  CAS  Google Scholar 

  11. Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Bourgeois, C., Rocha, B. & Tanchot, C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297, 2060–2063 (2002)

    Article  ADS  CAS  Google Scholar 

  15. Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Shedlock, D. J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003)

    Article  ADS  CAS  Google Scholar 

  17. Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003)

    Article  ADS  CAS  Google Scholar 

  18. Sun, J. C., Williams, M. A. & Bevan, M. J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nature Immunol. 5, 927–933 (2004)

    Article  CAS  Google Scholar 

  19. Cousens, L. P., Orange, J. S. & Biron, C. A. Endogenous IL-2 contributes to T cell expansion and IFN-γ production during lymphocytic choriomeningitis virus infection. J. Immunol. 155, 5690–5699 (1995)

    CAS  PubMed  Google Scholar 

  20. Kundig, T. M. et al. Immune responses in interleukin-2-deficient mice. Science 262, 1059–1061 (1993)

    Article  ADS  CAS  Google Scholar 

  21. D'Souza, W. N. & Lefrancois, L. IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J. Immunol. 171, 5727–5735 (2003)

    Article  CAS  Google Scholar 

  22. D'Souza, W. N., Schluns, K. S., Masopust, D. & Lefrancois, L. Essential role for IL-2 in the regulation of antiviral extralymphoid CD8 T cell responses. J. Immunol. 168, 5566–5572 (2002)

    Article  CAS  Google Scholar 

  23. Yu, A. et al. Efficient induction of primary and secondary T cell-dependent immune responses in vivo in the absence of functional IL-2 and IL-15 receptors. J. Immunol. 170, 236–242 (2003)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. 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 

  26. Marzo, A. L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nature Immunol. 6, 793–799 (2005)

    Article  ADS  CAS  Google Scholar 

  27. Boyman, O., Kovar, M., Rubinstein, M., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006)

    Article  ADS  CAS  Google Scholar 

  28. Granucci, F. et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nature Immunol. 2, 882–888 (2001)

    Article  CAS  Google Scholar 

  29. Ahmed, R., Salmi, A., Butler, L. D., Chiller, J. M. & Oldstone, M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160, 521–540 (1984)

    Article  CAS  Google Scholar 

  30. 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 

Download references

Acknowledgements

We thank B. Dere and X. Pan for technical assistance in the breeding, maintaining and typing of mouse colonies. The Howard Hughes Medical Institute and grants from the National Institutes of Health supported this work.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute and the Department of Immunology, University of Washington, Seattle, Washington, 98195, USA

    Matthew A. Williams, Aaron J. Tyznik & Michael J. Bevan

Authors
  1. Matthew A. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron J. Tyznik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael J. Bevan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J. Bevan.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1–8. The figures display 1) a schematic for our strategy for analysing immune responses by IL-2Rα-deficient T cells in TR-sufficient hosts, 2–3) two separate immunization strategies showing that both LCMV- and Listeria monocytogenes-primed IL-2Rα-deficient T cells make poor recall responses, 4) a schematic for generating naïve IL-2Rα-deficient P14 cells in a TR-sufficient host, 5) an analysis of responses by wt and IL-2Rα-deficient P14 cells in lymph nodes and liver, 6) an analysis of cytokine production and CD69-up-regulation by IL-2Rα-deficient P14 cells, 7) the tracking of P14 immune responses transferred at endogenous frequencies, and 8) immune responses by chimeras generated using a mixture of IL-2-deficient and wildtype bone marrow. (PDF 3142 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Williams, M., Tyznik, A. & Bevan, M. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441, 890–893 (2006). https://doi.org/10.1038/nature04790

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04790

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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