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:

Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo

Nature Medicine volume 9, pages 540–547 (2003)Cite this article

Abstract

Interleukin (IL)-2 is currently used to enhance T-cell immunity but can have both positive and negative effects on T cells. To determine whether these opposing results are due to IL-2 acting differently on T cells depending on their stage of differentiation, we examined the effects of IL-2 therapy during the expansion, contraction and memory phases of the T-cell response in lymphocytic choriomeningitis virus (LCMV)–infected mice. IL-2 treatment during the expansion phase was detrimental to the survival of rapidly dividing effector T cells. In contrast, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of virus-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells in mice that controlled the infection. Virus-specific T cells in chronically infected mice also responded to IL-2 resulting in decreased viral burden. Thus, timing of IL-2 administration and differentiation status of the T cell are critical parameters in designing IL-2 therapies.

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-2 therapy during the T-cell expansion phase.
Figure 2: IL-2 therapy during the T-cell contraction phase.
Figure 3: IL-2 causes increased proliferation and decreased apoptosis of T cells.
Figure 4: IL-2 therapy during the T-cell memory phase.
Figure 5: IL-2 therapy during chronic infection.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Gillis, S., Gillis, A.E. & Smith, K.A. The detection of a spleen focus-forming virus neoantigen by lymphocyte-mediated cytolysis. J. Exp. Med. 148, 18–31 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Van Parijs, L. et al. Uncoupling IL-2 signals that regulate T-cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity 11, 281–288 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Gillis, S. & Smith, K.A. Long term culture of tumour-specific cytotoxic T cells. Nature 268, 154–156 (1977).

    Article  CAS  PubMed  Google Scholar 

  5. Akbar, A.N. et al. Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T-cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression. Eur. J. Immunol. 26, 294–299 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Lenardo, M.J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858–861 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Barouch, D.H. et al. Augmentation of immune responses to HIV-1 and simian immunodeficiency virus DNA vaccines by IL-2/Ig plasmid administration in rhesus monkeys. Proc. Natl. Acad. Sci. USA 97, 4192–4197 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kuroda, K. et al. Implantation of IL-2-containing osmotic pump prolongs the survival of superantigen-reactive T cells expanded in mice injected with bacterial superantigen. J. Immunol. 157, 1422–1431 (1996).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. Dai, Z., Konieczny, B.T. & Lakkis, F.G. The dual role of IL-2 in the generation and maintenance of CD8+ memory T cells. J. Immunol. 165, 3031–3036 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. 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  PubMed  Google Scholar 

  15. Rosenberg, S.A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).

    Article  CAS  PubMed  Google Scholar 

  16. Kovacs, J.A. et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N. Engl. J. Med. 335, 1350–1356 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Kovacs, J.A. et al. Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy. Eur. J. Immunol. 31, 1351–1360 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Davey, R.T. et al. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: a randomized controlled trial. JAMA 284, 183–189 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Jacobson, E.L., Pilaro, F. & Smith, K.A. Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc. Natl. Acad. Sci. USA 93, 10405–10410 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Matloubian, M., Kolhekar, S.R., Somasundaram, T. & Ahmed, R. Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus. J. Virol. 67, 7340–7349 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zajac, A.J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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  PubMed  PubMed Central  Google Scholar 

  24. Wong, P. & Pamer, E.G. Antigen independent CD8 T-cell proliferation. J. Immunol. 166, 5864–5868 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. van Stipdonk, M.J., Lemmens, E.E. & Schoenberger, S.P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 381–382 (2001).

    Article  Google Scholar 

  26. von Herrath, M.G., Yokoyama, M., Dockter, J., Oldstone, M.B. & Whitton, J.L. CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. J. Virol. 70, 1072–1079 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lau, L.L., Jamieson, B.D., Somasundaram, T. & Ahmed, R. Cytotoxic T-cell memory without antigen. Nature 369, 648–652 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Grayson, J.M., Murali-Krishna, K., Altman, J.D. & Ahmed, R. Gene expression in antigen-specific CD8+ T cells during viral infection. J. Immunol. 166, 795–799 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Lotze, M.T. et al. In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J. Immunol. 135, 2865–2875 (1985).

    CAS  PubMed  Google Scholar 

  31. Lotze, M.T. et al. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer 58, 2764–2772 (1986).

    Article  CAS  PubMed  Google Scholar 

  32. Mier, J.W. et al. Induction of circulating tumor necrosis factor (TNF α) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients. J. Clin. Immunol. 8, 426–436 (1988).

    Article  CAS  PubMed  Google Scholar 

  33. Callan, M.F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J. Exp. Med. 187, 1395–1402 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wilson, J.D. et al. Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection. AIDS 14, 225–233 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Jin, X. et al. High frequency of cytomegalovirus-specific cytotoxic T-effector cells in HLA-A*0201-positive subjects during multiple viral coinfections. J. Infect. Dis. 181, 165–175 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Komanduri, K.V. et al. Direct measurement of CD4+ and CD8+ T-cell responses to CMV in HIV-1- infected subjects. Virology 279, 459–470 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. 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  PubMed  Google Scholar 

  38. Smith, K. Interleukin 2 immunotherapy. in Therapeutic Immunology (eds. Austen, F., Burakoff, S., Rosen, F. & Strom, T.) 240–250 (Blackwell Science, Oxford, UK, 2001).

    Google Scholar 

  39. Smith, K.A. et al. In vivo assessment of antiviral reactivity in chronic HIV infection. HIV Clin. Trials 1, 16–22 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Smith, K.A. To cure chronic HIV infection, a new therapeutic strategy is needed. Curr. Opin. Immunol. 13, 617–624 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Yee, C., Riddell, S.R. & Greenberg, P.D. Prospects for adoptive T-cell therapy. Curr. Opin. Immunol. 9, 702–708 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Whitmire, J.K. et al. CD40-CD40 ligand costimulation is required for generating antiviral CD4 T-cell responses but is dispensable for CD8 T-cell responses. J. Immunol. 163, 3194–3201 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank P.L. Mahar and other members of the Ahmed lab for helpful suggestions and technical assistance, and B.D. Evavold, P.D. Greenberg and L.E. Cheng for critical reading of this manuscript. This work was supported by National Institutes of Health grants AI30048 (to R.A.) and A151181 (to K.A.S.), the Cancer Research Institute/James E. Siegel Perpetual Fellowship Award (to J.N.B.), National Research Service Award 1F32AI0249-01A1 (to J.M.G.), a fellowship from the Cancer Research Institute (to E.J.W.), and the Cancer Research Fund of the Damon Runyon Cancer Research Foundation (DRG-1570 to S.M.K.).

Author information

Authors and Affiliations

  1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA

    Joseph N. Blattman, Jason M. Grayson, E. John Wherry, Susan M. Kaech & Rafi Ahmed

  2. Division of Immunology, Department of Medicine, Weill Medical College, Cornell University, New York, New York, USA

    Kendall A. Smith

Authors
  1. Joseph N. Blattman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason M. Grayson
    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. Susan M. Kaech
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kendall A. Smith
    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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blattman, J., Grayson, J., Wherry, E. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat Med 9, 540–547 (2003). https://doi.org/10.1038/nm866

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm866

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