1887

Abstract

The role of cytotoxic CD8 T cells is well defined in retroviral immunity but the role of CD4 T helper (Th) cells is poorly understood. The Friend retrovirus (FV) murine infection model is a good model to study immune responses in retroviral infections and hence was used to characterize the role of Th cells during acute infection. depletion of Th cells in acutely infected mice demonstrated that Th cells were vital in controlling viral spread and onset of erythroleukaemia and for the maintenance of FV-specific CD8 T-cell and neutralizing antibody responses. Kinetic analysis of FV-specific Th-cell responses using class-II tetramers showed that the magnitude of the Th-cell response correlated with the level of resistance to FV-induced leukaemia in different mouse strains. FV-specific CD4 T-cell receptor -transgenic (TCR-tg) T cells were adoptively transferred into mice infected for different time periods [1, 2 and 3 weeks post-infection (p.i.)] to investigate the direct antiviral effect of CD4 T cells in FV infection. Results indicated that FV-specific CD4 TCR-tg T cells were functionally active until 2 weeks p.i., retaining their ability to produce gamma interferon (IFN-) and reduce viral loads. However, the donor cells lost their antiviral activity starting from 3 weeks p.i. Interestingly, depletion of regulatory T cells (Tregs) at this time point restored IFN- production by transferred CD4 T cells. The current study reveals that Th cells were critical for recovery from acute FV infection but were functionally impaired during the late phase of acute infection due to induced Tregs.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.015834-0
2010-02-01
2019-11-17
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/2/440.html?itemId=/content/journal/jgv/10.1099/vir.0.015834-0&mimeType=html&fmt=ahah

References

  1. Altfeld, M. & Rosenberg, E. S. ( 2000; ). The role of CD4+ T helper cells in the cytotoxic T lymphocyte response to HIV-1. Curr Opin Immunol 12, 375–380.[CrossRef]
    [Google Scholar]
  2. Antunes, I., Tolaini, M., Kissenpfennig, A., Iwashiro, M., Kuribayashi, K., Malissen, B., Hasenkrug, K. & Kassiotis, G. ( 2008; ). Retrovirus-specificity of regulatory T cells is neither present nor required in preventing retrovirus-induced bone marrow immune pathology. Immunity 29, 782–794.[CrossRef]
    [Google Scholar]
  3. Buller, R. M., Holmes, K. L., Hugin, A., Frederickson, T. N. & Morse, H. C., III ( 1987; ). Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328, 77–79.[CrossRef]
    [Google Scholar]
  4. Cardin, R. D., Brooks, J. W., Sarawar, S. R. & Doherty, P. C. ( 1996; ). Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J Exp Med 184, 863–871.[CrossRef]
    [Google Scholar]
  5. Chesebro, B. & Wehrly, K. ( 1979; ). Identification of a non-H-2 gene (Rfv-3) influencing recovery from viremia and leukemia induced by Friend virus complex. Proc Natl Acad Sci U S A 76, 425–429.[CrossRef]
    [Google Scholar]
  6. Chesebro, B., Miyazawa, M. & Britt, W. J. ( 1990; ). Host genetic control of spontaneous and induced immunity to Friend murine retrovirus infection. Annu Rev Immunol 8, 477–499.[CrossRef]
    [Google Scholar]
  7. Dittmer, U. & Hasenkrug, K. J. ( 2000; ). Different immunological requirements for protection against acute versus persistent Friend retrovirus infections. Virology 272, 177–182.[CrossRef]
    [Google Scholar]
  8. Dittmer, U. & Hasenkrug, K. J. ( 2001; ). Cellular and molecular mechanisms of vaccine-induced protection against retroviral infections. Curr Mol Med 1, 431–436.[CrossRef]
    [Google Scholar]
  9. Dittmer, U., Brooks, D. M. & Hasenkrug, K. J. ( 1999; ). Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection. Nat Med 5, 189–193.[CrossRef]
    [Google Scholar]
  10. Dittmer, U., He, H., Messer, R. J., Schimmer, S., Olbrich, A. R., Ohlen, C., Greenberg, P. D., Stromnes, I. M., Iwashiro, M. & other authors ( 2004; ). Functional impairment of CD8+ T cells by regulatory T cells during persistent retroviral infection. Immunity 20, 293–303.[CrossRef]
    [Google Scholar]
  11. Estes, J. D., Li, Q., Reynolds, M. R., Wietgrefe, S., Duan, L., Schacker, T., Picker, L. J., Watkins, D. L., Lifson, J. D. & other authors ( 2006; ). Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis 193, 703–712.[CrossRef]
    [Google Scholar]
  12. Fayolle, C., Deriaud, E. & Leclerc, C. ( 1991; ). In vivo induction of cytotoxic T cell response by a free synthetic peptide requires CD4+ T cell help. J Immunol 147, 4069–4073.
    [Google Scholar]
  13. Franco, A., Guidotti, L. G., Hobbs, M. V., Pasquetto, V. & Chisari, F. V. ( 1997; ). Pathogenetic effector function of CD4-positive T helper 1 cells in hepatitis B virus transgenic mice. J Immunol 159, 2001–2008.
    [Google Scholar]
  14. Furci, L., Scarlatti, G., Burastero, S., Tambussi, G., Colognesi, C., Quillent, C., Longhi, R., Loverro, P., Borgonovo, B. & other authors ( 1997; ). Antigen-driven C-C chemokine-mediated HIV-1 suppression by CD4+ T cells from exposed uninfected individuals expressing the wild-type CCR-5 allele. J Exp Med 186, 455–460.[CrossRef]
    [Google Scholar]
  15. Gagnon, S. J., Ennis, F. A. & Rothman, A. L. ( 1999; ). Bystander target cell lysis and cytokine production by dengue virus-specific human CD4+ cytotoxic T-lymphocyte clones. J Virol 73, 3623–3629.
    [Google Scholar]
  16. Graham, M. B., Braciale, V. L. & Braciale, T. J. ( 1994; ). Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med 180, 1273–1282.[CrossRef]
    [Google Scholar]
  17. Hasenkrug, K. J. & Chesebro, B. ( 1997; ). Immunity to retroviral infection: the Friend virus model. Proc Natl Acad Sci U S A 94, 7811–7816.[CrossRef]
    [Google Scholar]
  18. Hasenkrug, K. J. & Dittmer, U. ( 2000; ). The role of CD4 and CD8 T cells in recovery and protection from retroviral infection: lessons from the Friend virus model. Virology 272, 244–249.[CrossRef]
    [Google Scholar]
  19. Hasenkrug, K. J., Brooks, D. M. & Dittmer, U. ( 1998a; ). Critical role for CD4+ T cells in controlling retrovirus replication and spread in persistently infected mice. J Virol 72, 6559–6564.
    [Google Scholar]
  20. Hasenkrug, K. J., Brooks, D. M., Robertson, M. N., Srinivas, R. V. & Chesebro, B. ( 1998b; ). Immunoprotective determinants in Friend murine leukemia virus envelope protein. Virology 248, 66–73.[CrossRef]
    [Google Scholar]
  21. He, H., Messer, R. J., Sakaguchi, S., Yang, G., Robertson, S. J. & Hasenkrug, K. J. ( 2004; ). Reduction of retrovirus-induced immunosuppression by in vivo modulation of T cells during acute infection. J Virol 78, 11641–11647.[CrossRef]
    [Google Scholar]
  22. Iwashiro, M., Messer, R. J., Peterson, K. E., Stromnes, I. M., Sugie, T. & Hasenkrug, K. J. ( 2001a; ). Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection. Proc Natl Acad Sci U S A 98, 9226–9230.[CrossRef]
    [Google Scholar]
  23. Iwashiro, M., Peterson, K. E., Messer, R. J., Stromnes, I. M. & Hasenkrug, K. J. ( 2001b; ). CD4+ T cells and gamma interferon in the long-term control of persistent friend retrovirus infection. J Virol 75, 52–60.[CrossRef]
    [Google Scholar]
  24. Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G. & Schoenberger, S. P. ( 2003; ). CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856.[CrossRef]
    [Google Scholar]
  25. Kaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D. & Ahmed, R. ( 2003; ). Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4, 1191–1198.[CrossRef]
    [Google Scholar]
  26. Lahl, K., Loddenkemper, C., Drouin, C., Freyer, J., Arnason, J., Eberl, G., Hamann, A., Wagner, H., Huehn, J. & Sparwasser, T. ( 2007; ). Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204, 57–63.[CrossRef]
    [Google Scholar]
  27. Littaua, R. A., Oldstone, M. B., Takeda, A. & Ennis, F. A. ( 1992; ). A CD4+ cytotoxic T-lymphocyte clone to a conserved epitope on human immunodeficiency virus type 1 p24: cytotoxic activity and secretion of interleukin-2 and interleukin-6. J Virol 66, 608–611.
    [Google Scholar]
  28. Lund, J. M., Hsing, L., Pham, T. T. & Rudensky, A. Y. ( 2008; ). Coordination of early protective immunity to viral infection by regulatory T cells. Science 320, 1220–1224.[CrossRef]
    [Google Scholar]
  29. Mahon, B. P., Katrak, K., Nomoto, A., Macadam, A. J., Minor, P. D. & Mills, K. H. ( 1995; ). Poliovirus-specific CD4+ Th1 clones with both cytotoxic and helper activity mediate protective humoral immunity against a lethal poliovirus infection in transgenic mice expressing the human poliovirus receptor. J Exp Med 181, 1285–1292.[CrossRef]
    [Google Scholar]
  30. Maloy, K. J., Burkhart, C., Freer, G., Rülicke, T., Pircher, H., Kono, D. H., Theofilopoulos, A. N., Ludewig, B., Hoffmann-Rohrer, U. & other authors ( 1999; ). Qualitative and quantitative requirements for CD4+ T cell-mediated antiviral protection. J Immunol 162, 2867–2874.
    [Google Scholar]
  31. Maloy, K. J., Burkhart, C., Junt, T. M., Odermatt, B., Oxenius, A., Piali, L., Zinkernagel, R. M. & Hengartner, H. ( 2000; ). CD4+ T cell subsets during virus infection. Protective capacity depends on effector cytokine secretion and on migratory capability. J Exp Med 191, 2159–2170.[CrossRef]
    [Google Scholar]
  32. Manickan, E., Rouse, R. J., Yu, Z., Wire, W. S. & Rouse, B. T. ( 1995; ). Genetic immunization against herpes simplex virus. Protection is mediated by CD4+ T lymphocytes. J Immunol 155, 259–265.
    [Google Scholar]
  33. Martin, M. P. & Carrington, M. ( 2005; ). Immunogenetics of viral infections. Curr Opin Immunol 17, 510–516.[CrossRef]
    [Google Scholar]
  34. Marzo, A. L., Vezys, V., Klonowski, K. D., Lee, S. J., Muralimohan, G., Moore, M., Tough, D. F. & Lefrancois, L. ( 2004; ). Fully functional memory CD8 T cells in the absence of CD4 T cells. J Immunol 173, 969–975.[CrossRef]
    [Google Scholar]
  35. Miyazawa, M., Nishio, J. & Chesebro, B. ( 1988; ). Genetic control of T cell responsiveness to the Friend murine leukemia virus envelope antigen. Identification of class II loci of the H-2 as immune response genes. J Exp Med 168, 1587–1605.[CrossRef]
    [Google Scholar]
  36. Miyazawa, M., Fujisawa, R., Ishihara, C., Takei, Y. A., Shimizu, T., Uenishi, H., Yamagishi, H. & Kuribayashi, K. ( 1995; ). Immunization with a single T helper cell epitope abrogates Friend virus-induced early erythroid proliferation and prevents late leukemia development. J Immunol 155, 748–758.
    [Google Scholar]
  37. Morrison, R. P., Earl, P. L., Nishio, J., Lodmell, D. L., Moss, B. & Chesebro, B. ( 1987; ). Different H-2 subregions influence immunization against retrovirus and immunosuppression. Nature 329, 729–732.[CrossRef]
    [Google Scholar]
  38. Norris, P. J., Sumaroka, M., Brander, C., Moffett, H. F., Boswell, S. L., Nguyen, T., Sykulev, Y., Walker, B. D. & Rosenberg, E. S. ( 2001; ). Multiple effector functions mediated by human immunodeficiency virus-specific CD4+ T-cell clones. J Virol 75, 9771–9779.[CrossRef]
    [Google Scholar]
  39. Novy, P., Quigley, M., Huang, X. & Yang, Y. ( 2007; ). CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses. J Immunol 179, 8243–8251.[CrossRef]
    [Google Scholar]
  40. Pantaleo, G. & Walker, B. D. ( 2001; ). Retroviral Immunology: Immune Response and Restoration. Totowa, NJ: Humana Press.
  41. Peterson, K. E., Iwashiro, M., Hasenkrug, K. J. & Chesebro, B. ( 2000; ). Major histocompatibility complex class I gene controls the generation of gamma interferon-producing CD4+ and CD8+ T cells important for recovery from Friend retrovirus-induced leukemia. J Virol 74, 5363–5367.[CrossRef]
    [Google Scholar]
  42. Poignard, P., Sabbe, R., Picchio, G. R., Wang, M., Gulizia, R. J., Katinger, H., Parren, P. W., Mosier, D. E. & Burton, D. R. ( 1999; ). Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438.[CrossRef]
    [Google Scholar]
  43. Pourbohloul, S. C., Thurlow, S. M., Furmanski, P. & Johnson, C. S. ( 1992; ). Induction of permanent regression of Friend virus (FV) leukemia by adoptive transfer of T helper and not T cytotoxic cells. Leuk Res 16, 881–887.[CrossRef]
    [Google Scholar]
  44. Reich, A., Erlwein, O., Niewiesk, S., ter Meulen, V. & Liebert, U. G. ( 1992; ). CD4+ T cells control measles virus infection of the central nervous system. Immunology 76, 185–191.
    [Google Scholar]
  45. Riberdy, J. M., Christensen, J. P., Branum, K. & Doherty, P. C. ( 2000; ). Diminished primary and secondary influenza virus-specific CD8+ T-cell responses in CD4-depleted Ig−/− mice. J Virol 74, 9762–9765.[CrossRef]
    [Google Scholar]
  46. Robertson, S. J. & Hasenkrug, K. J. ( 2006; ). The role of virus-induced regulatory T cells in immunopathology. Springer Semin Immunopathol 28, 51–62.[CrossRef]
    [Google Scholar]
  47. Robertson, M. N., Miyazawa, M., Mori, S., Caughey, B., Evans, L. H., Hayes, S. F. & Chesebro, B. ( 1991; ). Production of monoclonal antibodies reactive with a denatured form of the Friend murine leukemia virus gp70 envelope protein: use in a focal infectivity assay, immunohistochemical studies, electron microscopy and western blotting. J Virol Methods 34, 255–271.[CrossRef]
    [Google Scholar]
  48. Robertson, M. N., Spangrude, G. J., Hasenkrug, K., Perry, L., Nishio, J., Wehrly, K. & Chesebro, B. ( 1992; ). Role and specificity of T-cell subsets in spontaneous recovery from Friend virus-induced leukemia in mice. J Virol 66, 3271–3277.
    [Google Scholar]
  49. Robertson, S. J., Ammann, C. G., Messer, R. J., Carmody, A. B., Myers, L., Dittmer, U., Nair, S., Gerlach, N., Evans, L. H., Cafruny, W. A. & Hasenkrug, K. J. ( 2007; ). Suppression of acute anti-Friend virus CD8+ T cell responses by co-infection with lactate dehydrogenase-elevating virus. J Virol 82, 408–418.
    [Google Scholar]
  50. Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M., Boswell, S. L., Sax, P. E., Kalams, S. A. & Walker, B. D. ( 1997; ). Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450.[CrossRef]
    [Google Scholar]
  51. Sethi, K. K., Naher, H. & Stroehmann, I. ( 1988; ). Phenotypic heterogeneity of cerebrospinal fluid-derived HIV-specific and HLA-restricted cytotoxic T-cell clones. Nature 335, 178–181.[CrossRef]
    [Google Scholar]
  52. Shedlock, D. J. & Shen, H. ( 2003; ). Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339.[CrossRef]
    [Google Scholar]
  53. Smith, C. M., Wilson, N. S., Waithman, J., Villadangos, J. A., Carbone, F. R., Heath, W. R. & Belz, G. T. ( 2004; ). Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nat Immunol 5, 1143–1148.[CrossRef]
    [Google Scholar]
  54. Spiegel, H. M., Ogg, G. S., DeFalcon, E., Sheehy, M. E., Monard, S., Haslett, P. A., Gillespie, G., Donahoe, S. M., Pollack, H. & other authors ( 2000; ). Human immunodeficiency virus type 1- and cytomegalovirus-specific cytotoxic T lymphocytes can persist at high frequency for prolonged periods in the absence of circulating peripheral CD4(+) T cells. J Virol 74, 1018–1022.[CrossRef]
    [Google Scholar]
  55. Stromnes, I. M., Dittmer, U., Schumacher, T. N., Schepers, K., Messer, R. J., Evans, L. H., Peterson, K. E., Race, B. & Hasenkrug, K. J. ( 2002; ). Temporal effects of gamma interferon deficiency on the course of Friend retrovirus infection in mice. J Virol 76, 2225–2232.[CrossRef]
    [Google Scholar]
  56. Sun, J. C. & Bevan, M. J. ( 2003; ). Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342.[CrossRef]
    [Google Scholar]
  57. Varga, S. M. & Welsh, R. M. ( 1998; ). Stability of virus-specific CD4+ T cell frequencies from acute infection into long term memory. J Immunol 161, 367–374.
    [Google Scholar]
  58. 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. Curr Biol 4, 499–505.
    [Google Scholar]
  59. Yang, Y., Xiang, Z., Ertl, H. C. & Wilson, J. M. ( 1995; ). Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo. Proc Natl Acad Sci U S A 92, 7257–7261.[CrossRef]
    [Google Scholar]
  60. Zelinskyy, G., Balkow, S., Schimmer, S., Schepers, K., Simon, M. M. & Dittmer, U. ( 2004; ). Independent roles of perforin, granzymes, and Fas in the control of Friend retrovirus infection. Virology 330, 365–374.[CrossRef]
    [Google Scholar]
  61. Zelinskyy, G., Robertson, S. J., Schimmer, S., Messer, R. J., Hasenkrug, K. J. & Dittmer, U. ( 2005; ). CD8+ T-cell dysfunction due to cytolytic granule deficiency in persistent Friend retrovirus infection. J Virol 79, 10619–10626.[CrossRef]
    [Google Scholar]
  62. Zelinskyy, G., Kraft, A. R., Schimmer, S., Arndt, T. & Dittmer, U. ( 2006; ). Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection. Eur J Immunol 36, 2658–2670.[CrossRef]
    [Google Scholar]
  63. Zelinskyy, G., Dietze, K. K., Hüsecken, Y. P., Schimmer, S., Nair, S., Werner, T., Gibbert, K., Kershaw, O., Gruber, A. D. & other authors ( 2009; ). The regulatory T cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T cell response. Blood 114, 3199–3207.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.015834-0
Loading
/content/journal/jgv/10.1099/vir.0.015834-0
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