1887

Abstract

Using infections with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus in mice as model systems, we have investigated the ability of antigen-primed CD8 T cells generated in the context of viral infections to produce IL-2. Our results indicate that acute immunizing infection normally leads to generation of high numbers of IL-2-producing antigen-specific CD8 T cells. By costaining for IL-2 and IFN-γ intracellularly, we found that IL-2-producing cells predominantly constitute a subset of cells also producing IFN-γ. Comparison of the kinetics of generation revealed that IL-2-producing cells appear slightly delayed compared with the majority of IFN-γ producing cells, and the relative frequency of the IL-2-producing subset increases with transition into the memory phase. In contrast to acute immunizing infection, few IL-2-producing cells are generated during chronic LCMV infection. Furthermore, in MHC class II-deficient mice, which only transiently control LCMV infection, IL-2-producing CD8 T cells are initially generated, but by 4 weeks after infection this subset has nearly disappeared. Eventually the capacity to produce IFN-γ also becomes impaired, while cell numbers are maintained at a level similar to those in wild-type mice controlling the infection. Taken together, these findings indicate that phenotyping of T cell populations based on capacity to produce cytokines, and especially IL-2, can provide important information as to the functional status of the analysed cell subset. Specifically, combined analysis of the capacity to produce IL-2 and IFN-γ can be used as a predictor for loss of function within the CD8 T cell compartment.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-83-9-2123
2002-09-01
2019-10-21
Loading full text...

Full text loading...

/deliver/fulltext/jgv/83/9/0832123a.html?itemId=/content/journal/jgv/10.1099/0022-1317-83-9-2123&mimeType=html&fmt=ahah

References

  1. Ahmed, R., Butler, L. D. & Bhatti, L. ( 1988; ). T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. Journal of Virology 62, 2102-2106.
    [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. Journal of Immunology 164, 3689-3697.[CrossRef]
    [Google Scholar]
  3. Bachmann, M. F., Zinkernagel, R. M. & Oxenius, A. ( 1998; ). Immune responses in the absence of costimulation: viruses know the trick. Journal of Immunology 161, 5791-5794.
    [Google Scholar]
  4. Bartholdy, C., Christensen, J. P., Wodarz, D. & Thomsen, A. R. ( 2000; ). Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus. Journal of Virology 74, 10304-10311.[CrossRef]
    [Google Scholar]
  5. Bennett, S. R., Carbone, F. R., Karamalis, F., Flavell, R. A., Miller, J. F. & Heath, W. R. ( 1998; ). Help for cytotoxic-T-cell responses is mediated by CD40 signalling [see comments]. Nature 393, 478-480.[CrossRef]
    [Google Scholar]
  6. Bodmer, H., Obert, G., Chan, S., Benoist, C. & Mathis, D. ( 1993; ). Environmental modulation of the autonomy of cytotoxic T lymphocytes. European Journal of Immunology 23, 1649-1654.[CrossRef]
    [Google Scholar]
  7. Buller, R. M., Holmes, K. L., Hugin, A., Frederickson, T. N. & Morse, H. C. ( 1987; ). Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328, 77-79.[CrossRef]
    [Google Scholar]
  8. 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]
  9. Champagne, P., Ogg, G. S., King, A. S., Knabenhans, C., Ellefsen, K., Nobile, M., Appay, V., Rizzardi, G. P., Fleury, S., Lipp, M. & others ( 2001; ). Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111.[CrossRef]
    [Google Scholar]
  10. Christensen, J. P., Marker, O. & Thomsen, A. R. ( 1994; ). The role of CD4+ T cells in cell-mediated immunity to LCMV: studies in MHC class I and class II deficient mice. Scandinavian Journal of Immunology 40, 373-382.[CrossRef]
    [Google Scholar]
  11. 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. Journal of Immunology 166, 3384-3391.[CrossRef]
    [Google Scholar]
  12. Cousens, L. P., Orange, J. S. & Biron, C. A. ( 1995; ). Endogenous IL-2 contributes to T cell expansion and IFN-gamma production during lymphocytic choriomeningitis virus infection. Journal of Immunology 155, 5690-5699.
    [Google Scholar]
  13. den Boer, A. T., Diehl, L., van Mierlo, G. J., van der Voort, E. I., Fransen, M. F., Krimpenfort, P., Melief, C. J., Offringa, R. & Toes, R. E. ( 2001; ). Longevity of antigen presentation and activation status of APC are decisive factors in the balance between CTL immunity versus tolerance. Journal of Immunology 167, 2522-2528.[CrossRef]
    [Google Scholar]
  14. Ehl, S., Klenerman, P., Zinkernagel, R. M. & Bocharov, G. ( 1998; ). The impact of variation in the number of CD8+ T-cell precursors on the outcome of virus infection. Cellular Immunology 189, 67-73.[CrossRef]
    [Google Scholar]
  15. Gallimore, A., Glithero, A., Godkin, A., Tissot, A. C., Pluckthun, A., Elliott, T., Hengartner, H. & Zinkernagel, R. ( 1998; ). Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. Journal of Experimental Medicine 187, 1383-1393.[CrossRef]
    [Google Scholar]
  16. Gerlach, J. T., Diepolder, H. M., Jung, M. C., Gruener, N. H., Schraut, W. W., Zachoval, R., Hoffmann, R., Schirren, C. A., Santantonio, T. & Pape, G. R. ( 1999; ). Recurrence of hepatitis C virus after loss of virus-specific CD4+ T-cell response in acute hepatitis C. Gastroenterology 117, 933-941.[CrossRef]
    [Google Scholar]
  17. Gruener, N. H., Lechner, F., Jung, M. C., Diepolder, H., Gerlach, T., Lauer, G., Walker, B., Sullivan, J., Phillips, R., Pape, G. R. & others ( 2001; ). Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. Journal of Virology 75, 5550–5558.[CrossRef]
    [Google Scholar]
  18. Hudrisier, D., Oldstone, M. B. & Gairin, J. E. ( 1997; ). The signal sequence of lymphocytic choriomeningitis virus contains an immunodominant cytotoxic T cell epitope that is restricted by both H-2Db and H-2Kb molecules. Virology 234, 62-73.[CrossRef]
    [Google Scholar]
  19. 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. Journal of Experimental Medicine 186, 757-766.[CrossRef]
    [Google Scholar]
  20. Kasaian, M. T. & Biron, C. A. ( 1989; ). The activation of IL-2 transcription in L3T4+ and Lyt-2+ lymphocytes during virus infection in vivo. Journal of Immunology 142, 1287-1292.
    [Google Scholar]
  21. Ke, Y., Ma, H. & Kapp, J. A. ( 1998; ). Antigen is required for the activation of effector activities, whereas interleukin 2 is required for the maintenance of memory in ovalbumin- specific, CD8+ cytotoxic T lymphocytes. Journal of Experimental Medicine 187, 49-57.[CrossRef]
    [Google Scholar]
  22. Kennedy, M. K., Glaccum, M., Brown, S. N., Butz, E. A., Viney, J. L., Embers, M., Matsuki, N., Charrier, K., Sedger, L., Willis, C. R. & others ( 2000; ). Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. Journal of Experimental Medicine 191, 771–780.[CrossRef]
    [Google Scholar]
  23. Kostense, S., Ogg, G. S., Manting, E. H., Gillespie, G., Joling, J., Vandenberghe, K., Veenhof, E. Z., van Baarle, D., Jurriaans, S., Klein, M. R. and others ( 2001; ). High viral burden in the presence of major HIV-specific CD8+ T cell expansions: evidence for impaired CTL effector function. European Journal of Immunology 31, 677–686.[CrossRef]
    [Google Scholar]
  24. Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. ( 2000; ). Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675-678.[CrossRef]
    [Google Scholar]
  25. Lieberman, J., Shankar, P., Manjunath, N. & Andersson, J. ( 2001; ). Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98, 1667-1677.[CrossRef]
    [Google Scholar]
  26. Manjunath, N., Shankar, P., Wan, J., Weninger, W., Crowley, M. A., Hieshima, K., Springer, T. A., Fan, X., Shen, H., Lieberman, J. & others ( 2001; ). Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. Journal of Clinical Investigation 108, 871–878.[CrossRef]
    [Google Scholar]
  27. 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]
  28. Mizuochi, T., Hugin, A. W., Morse, H. C.III, Singer, A. & Buller, R. M. ( 1989; ). Role of lymphokine-secreting CD8+ T cells in cytotoxic T lymphocyte responses against vaccinia virus. Journal of Immunology 142, 270-273.
    [Google Scholar]
  29. Moskophidis, D., Cobbold, S. P., Waldmann, H. & Lehmann-Grube, F. ( 1987; ). 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. Journal of Virology 61, 1867-1874.
    [Google Scholar]
  30. Moskophidis, D., Lechner, F., Hengartner, H. & Zinkernagel, R. M. ( 1994; ). MHC class I and non-MHC-linked capacity for generating an anti-viral CTL response determines susceptibility to CTL exhaustion and establishment of virus persistence in mice. Journal of Immunology 152, 4976-4983.
    [Google Scholar]
  31. 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]
  32. 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-gamma-deficient mice infected with lymphocytic choriomeningitis virus. Journal of Immunology 163, 6114-6122.
    [Google Scholar]
  33. Oldstone, M. B., Whitton, J. L., Lewicki, H. & Tishon, A. ( 1988; ). Fine dissection of a nine amino acid glycoprotein epitope, a major determinant recognized by lymphocytic choriomeningitis virus-specific class I-restricted H-2Db cytotoxic T lymphocytes. Journal of Experimental Medicine 168, 559-570.[CrossRef]
    [Google Scholar]
  34. Oxenius, A., Bachmann, M. F., Ashton-Rickardt, P. G., Tonegawa, S., Zinkernagel, R. M. & Hengartner, H. ( 1995; ). Presentation of endogenous viral proteins in association with major histocompatibility complex class II: on the role of intracellular compartmentalization, invariant chain and the TAP transporter system. European Journal of Immunology 25, 3402-3411.[CrossRef]
    [Google Scholar]
  35. Ridge, J. P., Di Rosa, F. & Matzinger, P. ( 1998; ). A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell [see comments]. Nature 393, 474-478.[CrossRef]
    [Google Scholar]
  36. Rosenberg, A. S., Mizuochi, T. & Singer, A. ( 1986; ). Analysis of T-cell subsets in rejection of Kb mutant skin allografts differing at class I MHC. Nature 322, 829-831.[CrossRef]
    [Google Scholar]
  37. Saparov, A., Wagner, F. H., Zheng, R., Oliver, J. R., Maeda, H., Hockett, R. D. & Weaver, C. T. ( 1999; ). Interleukin-2 expression by a subpopulation of primary T cells is linked to enhanced memory/effector function. Immunity 11, 271-280.[CrossRef]
    [Google Scholar]
  38. Sarawar, S. R., Lee, B. J., Reiter, S. K. & Schoenberger, S. P. ( 2001; ). Stimulation via CD40 can substitute for CD4 T cell function in preventing reactivation of a latent herpesvirus. Proceedings of the National Academy of Sciences, USA 98, 6325-6329.[CrossRef]
    [Google Scholar]
  39. Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. ( 1998; ). T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions [see comments]. Nature 393, 480-483.[CrossRef]
    [Google Scholar]
  40. Schulz, M., Aichele, P., Vollenweider, M., Bobe, F. W., Cardinaux, F., Hengartner, H. & Zinkernagel, R. M. ( 1989; ). Major histocompatibility complex-dependent T cell epitopes of lymphocytic choriomeningitis virus nucleoprotein and their protective capacity against viral disease. European Journal of Immunology 19, 1657-1667.[CrossRef]
    [Google Scholar]
  41. Slifka, M. K. & Whitton, J. L. ( 2000; ). Activated and memory CD8+ T cells can be distinguished by their cytokine profiles and phenotypic markers. Journal of Immunology 164, 208-216.[CrossRef]
    [Google Scholar]
  42. Thomsen, A. R., Johansen, J., Marker, O. & Christensen, J. P. ( 1996; ). Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice. Journal of Immunology 157, 3074-3080.
    [Google Scholar]
  43. 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. Journal of Virology 74, 4429-4432.[CrossRef]
    [Google Scholar]
  44. Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A. & Rocha, B. ( 2000; ). Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nature Immunology 1, 47-53.[CrossRef]
    [Google Scholar]
  45. von Herrath, M. G., Yokoyama, M., Dockter, J., Oldstone, M. B. & Whitton, J. L. ( 1996; ). CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. Journal of Virology 70, 1072-1079.
    [Google Scholar]
  46. Wasik, T. J., Wierzbicki, A., Whiteman, V. E., Trinchieri, G., Lischner, H. W. & Kozbor, D. ( 2000; ). Association between HIV-specific T helper responses and CTL activities in pediatric AIDS. European Journal of Immunology 30, 117-127.[CrossRef]
    [Google Scholar]
  47. Wu, Y. & Liu, Y. ( 1994; ). Viral induction of co-stimulatory activity on antigen-presenting cells bypasses the need for CD4+ T-cell help in CD8+ T-cell responses. Current Biology 4, 499-505.
    [Google Scholar]
  48. Zajac, A. J., Blattman, J. N., Murali-Krishna, K., Sourdive, D. J., Suresh, M., Altman, J. D. & Ahmed, R. ( 1998; ). Viral immune evasion due to persistence of activated T cells without effector function. Journal of Experimental Medicine 188, 2205-2213.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-83-9-2123
Loading
/content/journal/jgv/10.1099/0022-1317-83-9-2123
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error