1887

Abstract

The ability of virus-specific CD8 T cells to produce cytokines was studied in mice infected with lymphocytic choriomeningitis virus and vesicular stomatitis virus. Intracellular staining was used to visualize cytokine-producing CD8 and CD4 T cells. Overall, virus-specific CD8 T cells produce a similar range of cytokines (IFN-, TNF-, IL-2, GM-CSF, RANTES, MIP-1 and MIP-1) as CD4 T cells, but the relative distribution of cytokine-producing subsets is different. Moreover, cytokine-producing CD8 T cells were found to dominate numerically at all time-points tested. Co-staining for more than one cytokine revealed that while all cytokine-producing CD8 T cells synthesized IFN-, additional cytokines were produced by partly overlapping subsets of this population. The frequency of cells producing more than one cytokine was higher in a tertiary site (peritoneum) and generally increased with transition into the memory phase; however, GM-CSF producing cells were only present transiently. Concerning factors predicted to influence the distribution of cytokine-producing subsets, IFN- and IL-12 did not play a role, nor was extensive virus replication essential. Notably, regarding the heterogeneity in cytokine production by individual cells with similar epitope specificity, variation in TCR avidity was not the cause, since -activated TCR transgene-expressing cells were as heterogeneous in cytokine expression as polyclonal cells specific for the same epitope.

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2004-06-01
2020-09-25
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References

  1. Andersen C., Jensen T., Nansen A., Marker O., Thomsen A. R. 1999; CD4+ T cell-mediated protection against a lethal outcome of systemic infection with vesicular stomatitis virus requires CD40 ligand expression, but not IFN-gamma or IL-4. Int Immunol 11:2035–2042 [CrossRef]
    [Google Scholar]
  2. Andreasen S. O., Christensen J. E., Marker O., Thomsen A. R. 2000; Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses. J Immunol 164:3689–3697 [CrossRef]
    [Google Scholar]
  3. Binder D., Kundig T. M. 1991; Antiviral protection by CD8+ versus CD4+ T cells. CD8+ T cells correlating with cytotoxic activity in vitro are more efficient in antivaccinia virus protection than CD4-dependent IL. J Immunol 146:4301–4307
    [Google Scholar]
  4. Butz E. A., Bevan M. J. 1998; Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 8:167–175 [CrossRef]
    [Google Scholar]
  5. Cerwenka A., Carter L. L., Reome J. B., Swain S. L., Dutton R. W. 1998; In vivo persistence of CD8 polarized T cell subsets producing type 1 or type 2 cytokines. J Immunol 161:97–105
    [Google Scholar]
  6. Christensen J. P., Ropke C., Thomsen A. R. 1996a; Virus-induced polyclonal T cell activation is followed by apoptosis: partitioning of CD8+ T cells based on alpha 4 integrin expression. Int Immunol 8:707–715 [CrossRef]
    [Google Scholar]
  7. Christensen J. P., Stenvang J. P., Marker O., Thomsen A. R. 1996b; Characterization of virus-primed CD8+ T cells with a type 1 cytokine profile. Int Immunol 8:1453–1461 [CrossRef]
    [Google Scholar]
  8. Christensen J. P., Bartholdy C., Wodarz D., Thomsen A. R. 2001; Depletion of CD4+ T cells precipitates immunopathology in immunodeficient mice infected with a noncytocidal virus. J Immunol 166:3384–3391 [CrossRef]
    [Google Scholar]
  9. Christensen J. E., Christensen J. P., Kristensen N. N., Hansen N. J., Stryhn A., Thomsen A. R. 2002; Role of CD28 co-stimulation in generation and maintenance of virus-specific T cells. Int Immunol 14:701–711 [CrossRef]
    [Google Scholar]
  10. Conlon K., Osborne J., Morimoto C., Ortaldo J. R., Young H. A. 1995; Comparison of lymphokine secretion and mRNA expression in the CD45RA+ and CD45RO+ subsets of human peripheral blood CD4+ and CD8+ lymphocytes. Eur J Immunol 25:644–648 [CrossRef]
    [Google Scholar]
  11. Croft M., Carter L., Swain S. L., Dutton R. W. 1994; Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med 180:1715–1728 [CrossRef]
    [Google Scholar]
  12. Foulds K. E., Zenewicz L. A., Shedlock D. J., Jiang J., Troy A. E., Shen H. 2002; Cutting edge: CD4 and CD8 T cells are intrinsically different in their proliferative responses. J Immunol 168:1528–1532 [CrossRef]
    [Google Scholar]
  13. Homann D., Teyton L., Oldstone M. B. 2001; Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat Med 7:913–919 [CrossRef]
    [Google Scholar]
  14. Itoh Y., Germain R. N. 1997; Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells. J Exp Med 186:757–766 [CrossRef]
    [Google Scholar]
  15. Kagi D., Hengartner H. 1996; Different roles for cytotoxic T cells in the control of infections with cytopathic versus noncytopathic viruses. Curr Opin Immunol 8:472–477 [CrossRef]
    [Google Scholar]
  16. Kagi D., Ledermann B., Burki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. 1994; Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37 [CrossRef]
    [Google Scholar]
  17. Kelso A., Glasebrook A. L., Kanagawa O., Brunner K. T. 1982; Production of macrophage-activating factor by T lymphocyte clones and correlation with other lymphokine activities. J Immunol 129:550–556
    [Google Scholar]
  18. Kristensen N. N., Christensen J. P., Thomsen A. R. 2002; High numbers of IL-2-producing CD8+ T cells during viral infection: correlation with stable memory development. J Gen Virol 83:2123–2133
    [Google Scholar]
  19. Le Gros G., Erard F. 1994; Non-cytotoxic, IL-4, IL-5, IL-10 producing CD8+ T cells: their activation and effector functions. Curr Opin Immunol 6:453–457 [CrossRef]
    [Google Scholar]
  20. Liew F. Y. 2002; TH1 and TH2 cells: a historical perspective. Nat Rev Immunol 2:55–60 [CrossRef]
    [Google Scholar]
  21. Lukacher A. E., Braciale V. L., Braciale T. J. 1984; In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 160:814–826 [CrossRef]
    [Google Scholar]
  22. Maggi E., Giudizi M. G., Biagiotti R. 8 other authors 1994; Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection. J Exp Med 180:489–495 [CrossRef]
    [Google Scholar]
  23. Marker O., Volkert M. 1973; Studies on cell-mediated immunity to lymphocytic choriomeningitis virus in mice. J Exp Med 137:1511–1525 [CrossRef]
    [Google Scholar]
  24. Marker O., Scheynius A., Christensen J. P., Thomsen A. R. 1995; Virus-activated T cells regulate expression of adhesion molecules on endothelial cells in sites of infection. J Neuroimmunol 62:35–42 [CrossRef]
    [Google Scholar]
  25. Masopust D., Vezys V., Marzo A. L., Lefrancois L. 2001; Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413–2417 [CrossRef]
    [Google Scholar]
  26. Morris A. G., Lin Y. L., Askonas B. A. 1982; Immune interferon release when a cloned cytotoxic T-cell line meets its correct influenza-infected target cell. Nature 295:150–152 [CrossRef]
    [Google Scholar]
  27. Mosmann T. R., Sad S. 1996; The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138–146 [CrossRef]
    [Google Scholar]
  28. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. 1986; Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357
    [Google Scholar]
  29. Murali-Krishna K., Altman J. D., Suresh M., Sourdive D. J., Zajac A. J., Miller J. D., Slansky J., Ahmed R. 1998; Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8:177–187 [CrossRef]
    [Google Scholar]
  30. Nansen A., Jensen T., Christensen J. P., Andreasen S. O., Ropke C., Marker O., Thomsen A. R. 1999; Compromised virus control and augmented perforin-mediated immunopathology in IFN- γ -deficient mice infected with lymphocytic choriomeningitis virus. J Immunol 163:6114–6122
    [Google Scholar]
  31. Oxenius A., Karrer U., Zinkernagel R. M., Hengartner H. 1999; IL-12 is not required for induction of type 1 cytokine responses in viral infections. J Immunol 162:965–973
    [Google Scholar]
  32. Paliard X., de Waal Malefijt R., Yssel H., Blanchard D., Chretien I., Abrams J., de Vries J., Spits H. 1988; Simultaneous production of IL-2, IL-4, and IFN- γ by activated human CD4+ and CD8+ T cell clones. J Immunol 141:849–855
    [Google Scholar]
  33. Pircher H., Burki K., Lang R., Hengartner H., Zinkernagel R. M. 1989; Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342:559–561 [CrossRef]
    [Google Scholar]
  34. Prystowsky M. B., Ely J. M., Beller D. I. 9 other authors 1982; Alloreactive cloned T cell lines. VI. Multiple lymphokine activities secreted by helper and cytolytic cloned T lymphocytes. J Immunol 129:2337–2344
    [Google Scholar]
  35. Ruedl C., Kopf M., Bachmann M. F. 1999; CD8+ T cells mediate CD40-independent maturation of dendritic cells in vivo. J Exp Med 189:1875–1884 [CrossRef]
    [Google Scholar]
  36. Sad S., Marcotte R., Mosmann T. R. 1995; Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity 2:271–279 [CrossRef]
    [Google Scholar]
  37. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. 1991; Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254:279–282 [CrossRef]
    [Google Scholar]
  38. Schijns V. E., Haagmans B. L., Rijke E. O., Huang S., Aguet M., Horzinek M. C. 1994; IFN- γ receptor-deficient mice generate antiviral Th1-characteristic cytokine profiles but altered antibody responses. J Immunol 153:2029–2037
    [Google Scholar]
  39. Slifka M. K., Whitton J. L. 2000; Activated and memory CD8+ T cells can be distinguished by their cytokine profiles and phenotypic markers. J Immunol 164:208–216 [CrossRef]
    [Google Scholar]
  40. Thomsen A. R., Nansen A., Andersen C., Johansen J., Marker O., Christensen J. P. 1997; Cooperation of B cells and T cells is required for survival of mice infected with vesicular stomatitis virus. Int Immunol 9:1757–1766 [CrossRef]
    [Google Scholar]
  41. Valitutti S., Muller S., Dessing M., Lanzavecchia A. 1996; Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med 183:1917–1921 [CrossRef]
    [Google Scholar]
  42. Varga S. M., Welsh R. M. 2000; High frequency of virus-specific interleukin-2-producing CD4+ T cells and Th1 dominance during lymphocytic choriomeningitis virus infection. J Virol 74:4429–4432 [CrossRef]
    [Google Scholar]
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