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Rapid on/off cycling of cytokine production by virus-specific CD8+ T cells

Nature volume 401, pages 76–79 (1999)Cite this article

Abstract

CD8-positive T cells protect the body against viral pathogens by two important mechanisms: production of antiviral cytokines1,2 and lysis of infected cells3,4. Cytokine production can have both local and systemic consequences5,6, whereas cytolytic activity is limited to infected cells that are in direct contact with T cells7,8,9. Here we analyse activated CD8-positive T cells from mice infected with lymphocytic choriomeningitis virus and find that cytokines are not produced ex vivo in the absence of peptide stimulation, but that they are rapidly generated after T cells encounter viral peptides bound to the major histocompatibility complex. Remarkably, cytokine production ceases immediately upon dissociation of the T cells from their targets and resumes when antigenic contact is restored. In contrast to the ‘on/off/on’ cycling of cytokines, the pore-forming cytotoxic protein perforin is constitutively maintained. Our results indicate that there is differential expression of effector molecules according to whether the antiviral product is secreted (like cytokines) or stored inside the cell (like perforin). The ability to turn cytokines on and off while maintaining intracellular stores of perforin shows the versatility of the cellular immune response and provides a mechanism for maintaining effective immune surveillance while reducing systemic immunopathology.

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Figure 1: Perforin expression in virus-specific CD8+ T cells.
Figure 2: Kinetics of virus-specific cytokine production.
Figure 3: Rapid on/off/on cycling of cytokine production by activated CD8+ T cells.

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References

  1. Ramsay,A. J., Ruby,J. & Ramshaw,I. A. A case for cytokines as effector molecules in the resolution of virus infection. Immunol. Today 14, 155–157 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Guidotti,L. G. & Chisari,F. V. To kill or to cure: options in host defense against viral infection. Curr. Opin. Immunol. 8, 478–483 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Walsh,C. M. et al. Immune fucntion in mice lacking the perforin gene. Proc. Natl Acad. Sci. USA 91, 10854–10858 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kagi,D. et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369, 31–37 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Vassalli,P. The pathophysiology of tumor necrosis factors. Annu. Rev. Immunol. 10, 411–452 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Tracey,K. J. et al. Shock and tissue injury induced by recombinant human cachectin. Science 234, 470–474 (1986).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Lowin,B., Hahne,M., Mattmann,C. & Tschopp,J. Cytolytic T-cell cytoxicity is mediated through perforin and Fas lytic pathways. Nature 370, 650–652 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Bossi,G. & Griffiths,G. M. Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells. Nature Med. 5, 90–96 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Hahn,K. et al. Antigen presentation and cytotoxic T lymphocyte killing studied in individual, living cells. Virology 201, 330–340 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Whitton,J. L. & Oldstone,M. B. A. in Fields' Virology Vol. 3 (eds Fields, B. N., Knipe, D. M. & Howley, P. M.) 345–374 (Raven, New York, 1996).

    Google Scholar 

  11. Ahmed,R. et al. 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  PubMed  Google Scholar 

  12. Byrne,J. A. & Oldstone,M. B. A. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J. Virol. 51, 682–686 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Moskophidis,D., Cobbold,S. P., Waldmann,H. & Lehmann-Grube,F. Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response. J. Virol. 61, 1867–1874 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Whitton,J. L. Lymphocytic choriomeningitis virus CTL. Semin. Virol. 1, 257–262 (1990).

    Google Scholar 

  15. Schulz,M. et al. Major histocompatibility complex-dependent T cell epitopes of lymphocytic choriomeningitis virus nucleoprotein and their protective capacity against viral disease. Eur. J. Immunol. 19, 1657–1668 (1998).

    Article  Google Scholar 

  16. Butz,E. A. & Bevan,M. J. Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 8, 167–175 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 

  18. Whitton,J. L. et al. Molecular analyses of a five-amino-acid cytotoxic T-lymphocyte (CTL) epitope: an immunodominant region which induces nonreciprocal CTL cross-reactivity. J. Virol. 63, 4303–4310 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang,Y., Chang,J. F., Parnes,J. R. & Fathman,C. G. T cell receptor (TCR) engagement leads to activation-induced splicing of tumor necrosis factor (TNF) nuclear pre-mRNA. J. Exp. Med. 188, 247–254 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Flynn,K. J. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683–691 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Sachs,A. B. Messenger RNA degradation in eukaryotes. Cell 74, 413–421 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Hayden,F. G. et al. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J. Clin. Invest. 101, 643–649 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Campbell,I. L. Neuropathogenic actions of cytokines assessed in transgenic mice. Int. J. Dev. Neurosci. 13, 275–284 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Masuda,N. et al. Interleukin 6 is a cause of flu-like symptoms in treatment with a deoxycytidine analogue. Br. J. Cancer 78, 388–389 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Selin,L. K., Varga,S. M., Wong,I. C. & Welsh,R. M. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J. Exp. Med. 188, 1705–1715 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tracey,K. J. & Cerami,A. Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels. Proc. Soc. Exp. Biol. Med. 200, 233–239 (1992).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Lord for administrative assistance. The work was supported by grants from the NIH (J.L.W. and M.K.S.) and by Eusko Juarlaritza (F.R.).

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  1. Department of Neuropharmacology, CVN-9, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, 92037, California, USA

    Mark K. Slifka, Fernando Rodriguez & J. Lindsay Whitton

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  1. Mark K. Slifka
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  2. Fernando Rodriguez
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Correspondence to Mark K. Slifka.

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Slifka, M., Rodriguez, F. & Whitton, J. Rapid on/off cycling of cytokine production by virus-specific CD8+ T cells. Nature 401, 76–79 (1999). https://doi.org/10.1038/43454

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