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:

IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages

Nature Medicine volume 8, pages 166–170 (2002)Cite this article

Abstract

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen.

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: Role of CD4+ cells in the development of CD8+ T cell responses.
Figure 2: Initial proliferation of antigen-activated CD8+ T cells is not affected by the absence of CD4+ T cells.
Figure 3: Development of CD8+ T cell responses requires IL-4.
Figure 4: Neutralization of IL-4 by antibody treatment reduces the CD8+ T-cell response.

Similar content being viewed by others

References

  1. Cardin, R.D., Brooks, J. W., Sarawar, S.R. & Doherty, P.C. Progressive loss of CD8+ T cell–mediated control of a γ-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184, 863–871 (1996).

    Article  CAS  Google Scholar 

  2. Riberdy, J.M., Christensen, J.P., Branum, K. & Doherty, P.C. Diminished primary and secondary influenza virus–specific CD8+ T-cell responses in CD4-depleted Ig−/− mice. J. Virol. 74, 9762–9765 (2000).

    Article  CAS  Google Scholar 

  3. Ossendorp, F., Mengede, E., Camps, M., Filius, R. & Melief, C.J. Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. J. Exp. Med. 187, 693–702 (1998).

    Article  CAS  Google Scholar 

  4. Kurts, C. et al. CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity. J. Exp. Med. 186, 2057–2062 (1997).

    Article  CAS  Google Scholar 

  5. Keene, J.A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 (1982).

    Article  CAS  Google Scholar 

  6. Ridge, J.P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  CAS  Google Scholar 

  7. Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).

    Article  CAS  Google Scholar 

  8. Schoenberger, S.P., Toes, R.E., van der Voort, E.I., Offringa, R. & Melief, C.J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).

    Article  CAS  Google Scholar 

  9. Franco, A. et al. Epitope affinity for MHC class I determines helper requirement for CTL priming. Nature Immunol. 1, 145–150 (2000).

    Article  CAS  Google Scholar 

  10. Lu, Z. et al. CD40-independent pathways of T cell help for priming of CD8+ cytotoxic T lymphocytes. J. Exp. Med. 191, 541–550 (2000).

    Article  CAS  Google Scholar 

  11. Buller, R.M., Holmes, K.L., Hugin, A., Frederickson, T.N. & Morse, H.C. 3rd. Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328, 77–79 (1987).

    Article  CAS  Google Scholar 

  12. Peng, L. et al. Helper-independent, L-selectinlow CD8+ T cells with broad anti-tumor efficacy are naturally sensitized during tumor progression. J. Immunol. 165, 5738–5749 (2000).

    Article  CAS  Google Scholar 

  13. Allan, W., Tabi, Z., Cleary, A. & Doherty, P.C. Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J. Immunol. 144, 3980–3986 (1990).

    CAS  PubMed  Google Scholar 

  14. Bodmer, H., Obert, G., Chan, S., Benoist, C. & Mathis, D. Environmental modulation of the autonomy of cytotoxic T lymphocytes. Eur. J. Immunol. 23, 1649–1654 (1993).

    Article  CAS  Google Scholar 

  15. Tripp, R.A., Sarawar, S.R. & Doherty, P.C. Characteristics of the influenza virus–specific CD8+ T cell response in mice homozygous for disruption of the H-2lAb gene. J. Immunol. 155, 2955–2959 (1995).

    CAS  PubMed  Google Scholar 

  16. Andreasen, S.O., Christensen, J.E., Marker, O. & Thomsen, A.R. Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses. J. Immunol. 164, 3689–3697 (2000).

    Article  CAS  Google Scholar 

  17. Borrow, P. et al. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J. Exp. Med. 183, 2129–2142 (1996).

    Article  CAS  Google Scholar 

  18. Romero, P. et al. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341, 323–326 (1989).

    Article  CAS  Google Scholar 

  19. Rodrigues, M.M. et al. CD8+ cytolytic T cell clones derived against the Plasmodium yoelii circumsporozoite protein protect against malaria. Int. Immunol. 3, 579–585 (1991).

    Article  CAS  Google Scholar 

  20. Zavala, F. et al. A striking property of recombinant poxviruses: Efficient inducers of in vivo expansion of primed CD8+ T cells. Virology 280, 155–159 (2001).

    Article  CAS  Google Scholar 

  21. Sano, G. et al. Swift development of protective effector functions in naive CD8+ T cells against malaria liver stages. J. Exp. Med. 194, 173–180 (2001).

    Article  CAS  Google Scholar 

  22. Weiss, W.R., Sedegah, M., Berzofsky, J.A. & Hoffman, S.L. The role of CD4+ T cells in immunity to malaria sporozoites. J. Immunol. 151, 2690–2698 (1993).

    CAS  PubMed  Google Scholar 

  23. Miyahira, Y. et al. Quantification of antigen specific CD8+ T cells using an ELISPOT assay. J. Immunol. Methods 181, 45–54 (1995).

    Article  CAS  Google Scholar 

  24. Carvalho, L.H., Hafalla, J.C. & Zavala, F. ELISPOT assay to measure antigen-specific murine CD8+ T cell responses. J. Immunol. Methods 252, 207–218 (2001).

    Article  CAS  Google Scholar 

  25. Ohteki, T. & MacDonald, H.R. Major histocompatibility complex class I related molecules control the development of CD4+8− and CD4−8− subsets of natural killer 1.1+ T cell receptor-α/β+ cells in the liver of mice. J. Exp. Med. 180, 699–704 (1994).

    Article  CAS  Google Scholar 

  26. Seaman, W.E., Sleisenger, M., Eriksson, E. & Koo, G.C. Depletion of natural killer cells in mice by monoclonal antibody to NK-1.1. Reduction in host defense against malignancy without loss of cellular or humoral immunity. J. Immunol. 138, 4539–4544 (1987).

    CAS  Google Scholar 

  27. Lyons, A.B. & Parish, C.R. Determination of lymphocyte division by flow cytometry. J. Immunol. Methods 171, 131–137 (1994).

    Article  CAS  Google Scholar 

  28. Kaplan, M.H. & Grusby, M.J. Regulation of T helper cell differentiation by STAT molecules. J. Leukoc. Biol. 64, 2–5 (1998).

    Article  CAS  Google Scholar 

  29. Schluns, K.S., Kieper, W.C., Jamenson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000).

    Article  CAS  Google Scholar 

  30. Pedras-Vasconcelos, J.A. & Pearce, E.J. Type 1 CD8+ T cell responses during infection with the helminth Schistosoma mansoni. J. Immunol. 157, 3046–3053 (1996).

    CAS  PubMed  Google Scholar 

  31. Huang, L.R., Chen, F.L., Chen, Y.T., Lin, Y.M. & Kung, J.T. Potent induction of long-term CD8+ T cell memory by short-term IL-4 exposure during T cell receptor stimulation. Proc. Natl. Acad. Sci. USA. 97, 3406–3411 (2000).

    Article  CAS  Google Scholar 

  32. Schuler, T., Qin, Z., Ibe, S., Noben-Trauth, N. & Blankenstein, T. T helper cell type 1–associated and cytotoxic T lymphocyte–mediated tumor immunity is impaired in interleukin 4–deficient mice. J. Exp. Med. 189, 803–810 (1999).

    Article  CAS  Google Scholar 

  33. Armitage, R.J., Beckmann, M.P., Idzerda, R.L., Alpert, A. & Fanslow, W.C. Regulation of interleukin 4 receptors on human T cells. Int. Immunol. 2, 1039–1045 (1990).

    Article  CAS  Google Scholar 

  34. Paul, W.E. & Seder, R.A. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).

    Article  CAS  Google Scholar 

  35. Bucy, R.P. & Kilby, J.M. Perspectives on inducing efficient immune control of HIV-1 replication—a new goal for HIV therapeutics? AIDS 15 Suppl 2, S36–S42 (2001).

    Article  CAS  Google Scholar 

  36. McCune, J.M. The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410, 974–979 (2001).

    Article  CAS  Google Scholar 

  37. Dialynas, D.P. et al. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: Similarity of L3T4 to the human Leu-3/T4 molecule. J. Immunol. 131, 2445–2451 (1983).

    CAS  Google Scholar 

  38. Ohara, J. & Paul, W.E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature 315, 333–336 (1985).

    Article  CAS  Google Scholar 

  39. Altman, J.D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. and V. Nussenzweig for support and encouragement; B. Waksman, G. Milon and J.J. Lafaille for exciting and helpful discussions; and D. Eichinger, J. Peterson and J. Schmieg for reviewing the manuscript. This work was supported by the US National Institutes of Health. L.H.C. is a fellow of CNPq (Brazil).

Author information

Author notes

  1. Luzia H. Carvalho and Gen-ichiro Sano: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York, USA

    Luzia H. Carvalho, Gen-ichiro Sano, Julius C.R. Hafalla, Alexandre Morrot & Fidel Zavala

  2. Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    Maria A. Curotto de Lafaille

Authors
  1. Luzia H. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gen-ichiro Sano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julius C.R. Hafalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandre Morrot
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria A. Curotto de Lafaille
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fidel Zavala
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fidel Zavala.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carvalho, L., Sano, Gi., Hafalla, J. et al. IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages. Nat Med 8, 166–170 (2002). https://doi.org/10.1038/nm0202-166

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0202-166

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