Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1993 Dec;67(12):7623–7628. doi: 10.1128/jvi.67.12.7623-7628.1993

Effects of virally expressed interleukin-10 on vaccinia virus infection in mice.

M G Kurilla 1, S Swaminathan 1, R M Welsh 1, E Kieff 1, R R Brutkiewicz 1
PMCID: PMC238230  PMID: 8230481

Abstract

To investigate the in vivo role of interleukin-10 (IL-10) in viral infection, we compared infections with a recombinant vaccinia virus (VV) expressing IL-10 (VV-IL10) under control of the VV P7.5 promoter and a control virus (VV-beta gal) in normal and severe combined immunodeficient mice. In normal mice, VV-IL10 infection resulted in less natural killer cell activity at 3 days postinfection and less VV-specific cytotoxic T-cell activity at 6 or 7 days postinfection than VV-beta gal infection. However, the use of dermal scarification or intraperitoneal, intranasal, or intracerebral inoculation into immunocompetent mice resulted in no difference between VV-IL10 and VV-beta gal in visible lesions, mortality, protective immunity to a 100-fold lethal VV challenge, or VV-specific antibody response. In the immunodeficient mice, VV-IL10 infection resulted in greater natural killer cell activity and lower virus replication than VV-beta gal infection. These in vivo effects were subtler and more complex than had been anticipated. From the VV-IL10 murine model, the Epstein-Barr virus-encoded homolog of human IL-10, BCRF1, may provide a selective advantage by blunting the early human natural killer cell and cytotoxic T-cell responses so that Epstein-Barr virus can establish a well-contained latent infection in B lymphocytes.

Full text

PDF
7623

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BENNETT B. M. Estimation of LD50 by moving averages. J Hyg (Lond) 1952 Jun;50(2):157–164. doi: 10.1017/s0022172400019513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bancroft G. J., Schreiber R. D., Unanue E. R. Natural immunity: a T-cell-independent pathway of macrophage activation, defined in the scid mouse. Immunol Rev. 1991 Dec;124:5–24. doi: 10.1111/j.1600-065x.1991.tb00613.x. [DOI] [PubMed] [Google Scholar]
  3. Biron C. A., Welsh R. M. Blastogenesis of natural killer cells during viral infection in vivo. J Immunol. 1982 Dec;129(6):2788–2795. [PubMed] [Google Scholar]
  4. Blanden R. V. Mechanisms of recovery from a generalized viral infection: mousepox. I. The effects of anti-thymocyte serum. J Exp Med. 1970 Nov;132(5):1035–1054. doi: 10.1084/jem.132.5.1035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boom W. H., Liano D., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. II. Effects of interleukin 4- and interleukin 2-producing T cell clones on resting B lymphocytes. J Exp Med. 1988 Apr 1;167(4):1350–1363. doi: 10.1084/jem.167.4.1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bukowski J. F., McIntyre K. W., Yang H., Welsh R. M. Natural killer cells are not required for interferon-mediated prophylaxis against vaccinia or murine cytomegalovirus infections. J Gen Virol. 1987 Aug;68(Pt 8):2219–2222. doi: 10.1099/0022-1317-68-8-2219. [DOI] [PubMed] [Google Scholar]
  8. Buller R. M., Palumbo G. J. Poxvirus pathogenesis. Microbiol Rev. 1991 Mar;55(1):80–122. doi: 10.1128/mr.55.1.80-122.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buller R. M., Smith G. L., Cremer K., Notkins A. L., Moss B. Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative phenotype. 1985 Oct 31-Nov 6Nature. 317(6040):813–815. doi: 10.1038/317813a0. [DOI] [PubMed] [Google Scholar]
  10. Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
  12. Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  14. Flexner C., Hügin A., Moss B. Prevention of vaccinia virus infection in immunodeficient mice by vector-directed IL-2 expression. Nature. 1987 Nov 19;330(6145):259–262. doi: 10.1038/330259a0. [DOI] [PubMed] [Google Scholar]
  15. Go N. F., Castle B. E., Barrett R., Kastelein R., Dang W., Mosmann T. R., Moore K. W., Howard M. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med. 1990 Dec 1;172(6):1625–1631. doi: 10.1084/jem.172.6.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hasler F., Bluestein H. G., Zvaifler N. J., Epstein L. B. Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation. J Exp Med. 1983 Jan 1;157(1):173–188. doi: 10.1084/jem.157.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hsu D. H., Moore K. W., Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol. 1992 May;4(5):563–569. doi: 10.1093/intimm/4.5.563. [DOI] [PubMed] [Google Scholar]
  18. Hsu D. H., de Waal Malefyt R., Fiorentino D. F., Dang M. N., Vieira P., de Vries J., Spits H., Mosmann T. R., Moore K. W. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science. 1990 Nov 9;250(4982):830–832. doi: 10.1126/science.2173142. [DOI] [PubMed] [Google Scholar]
  19. Karupiah G., Blanden R. V., Ramshaw I. A. Interferon gamma is involved in the recovery of athymic nude mice from recombinant vaccinia virus/interleukin 2 infection. J Exp Med. 1990 Nov 1;172(5):1495–1503. doi: 10.1084/jem.172.5.1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Karupiah G., Coupar B. E., Andrew M. E., Boyle D. B., Phillips S. M., Müllbacher A., Blanden R. V., Ramshaw I. A. Elevated natural killer cell responses in mice infected with recombinant vaccinia virus encoding murine IL-2. J Immunol. 1990 Jan 1;144(1):290–298. [PubMed] [Google Scholar]
  21. Killar L., MacDonald G., West J., Woods A., Bottomly K. Cloned, Ia-restricted T cells that do not produce interleukin 4(IL 4)/B cell stimulatory factor 1(BSF-1) fail to help antigen-specific B cells. J Immunol. 1987 Mar 15;138(6):1674–1679. [PubMed] [Google Scholar]
  22. Klein G., Klein E. The changing faces of EBV research. Prog Med Virol. 1984;30:87–106. [PubMed] [Google Scholar]
  23. Kohonen-Corish M. R., King N. J., Woodhams C. E., Ramshaw I. A. Immunodeficient mice recover from infection with vaccinia virus expressing interferon-gamma. Eur J Immunol. 1990 Jan;20(1):157–161. doi: 10.1002/eji.1830200123. [DOI] [PubMed] [Google Scholar]
  24. Lotz M., Tsoukas C. D., Fong S., Carson D. A., Vaughan J. H. Regulation of Epstein-Barr virus infection by recombinant interferons. Selected sensitivity to interferon-gamma. Eur J Immunol. 1985 May;15(5):520–525. doi: 10.1002/eji.1830150518. [DOI] [PubMed] [Google Scholar]
  25. Masucci M. G., Bejarano M. T., Masucci G., Klein E. Large granular lymphocytes inhibit the in vitro growth of autologous Epstein-Barr virus-infected B cells. Cell Immunol. 1983 Mar;76(2):311–321. doi: 10.1016/0008-8749(83)90374-x. [DOI] [PubMed] [Google Scholar]
  26. Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
  27. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  28. Mosmann T. R., Moore K. W. The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today. 1991 Mar;12(3):A49–A53. doi: 10.1016/S0167-5699(05)80015-5. [DOI] [PubMed] [Google Scholar]
  29. Mosmann T. R., Schumacher J. H., Fiorentino D. F., Leverah J., Moore K. W., Bond M. W. Isolation of monoclonal antibodies specific for IL-4, IL-5, IL-6, and a new Th2-specific cytokine (IL-10), cytokine synthesis inhibitory factor, by using a solid phase radioimmunoadsorbent assay. J Immunol. 1990 Nov 1;145(9):2938–2945. [PubMed] [Google Scholar]
  30. Murray R. J., Kurilla M. G., Griffin H. M., Brooks J. M., Mackett M., Arrand J. R., Rowe M., Burrows S. R., Moss D. J., Kieff E. Human cytotoxic T-cell responses against Epstein-Barr virus nuclear antigens demonstrated by using recombinant vaccinia viruses. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2906–2910. doi: 10.1073/pnas.87.8.2906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pross H. F., Baines M. G., Rubin P., Shragge P., Patterson M. S. Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol. 1981 Jan;1(1):51–63. doi: 10.1007/BF00915477. [DOI] [PubMed] [Google Scholar]
  32. Ramshaw I. A., Andrew M. E., Phillips S. M., Boyle D. B., Coupar B. E. Recovery of immunodeficient mice from a vaccinia virus/IL-2 recombinant infection. Nature. 1987 Oct 8;329(6139):545–546. doi: 10.1038/329545a0. [DOI] [PubMed] [Google Scholar]
  33. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ruby J., Ramshaw I. The antiviral activity of immune CD8+ T cells is dependent on interferon-gamma. Lymphokine Cytokine Res. 1991 Oct;10(5):353–358. [PubMed] [Google Scholar]
  35. Sambhi S. K., Kohonen-Corish M. R., Ramshaw I. A. Local production of tumor necrosis factor encoded by recombinant vaccinia virus is effective in controlling viral replication in vivo. Proc Natl Acad Sci U S A. 1991 May 1;88(9):4025–4029. doi: 10.1073/pnas.88.9.4025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Stewart J. P., Rooney C. M. The interleukin-10 homolog encoded by Epstein-Barr virus enhances the reactivation of virus-specific cytotoxic T cell and HLA-unrestricted killer cell responses. Virology. 1992 Dec;191(2):773–782. doi: 10.1016/0042-6822(92)90253-l. [DOI] [PubMed] [Google Scholar]
  37. Stout R. D., Bottomly K. Antigen-specific activation of effector macrophages by IFN-gamma producing (TH1) T cell clones. Failure of IL-4-producing (TH2) T cell clones to activate effector function in macrophages. J Immunol. 1989 Feb 1;142(3):760–765. [PubMed] [Google Scholar]
  38. Thompson-Snipes L., Dhar V., Bond M. W., Mosmann T. R., Moore K. W., Rennick D. M. Interleukin 10: a novel stimulatory factor for mast cells and their progenitors. J Exp Med. 1991 Feb 1;173(2):507–510. doi: 10.1084/jem.173.2.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tomkinson B. E., Wagner D. K., Nelson D. L., Sullivan J. L. Activated lymphocytes during acute Epstein-Barr virus infection. J Immunol. 1987 Dec 1;139(11):3802–3807. [PubMed] [Google Scholar]
  40. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Welsh R. M., Brubaker J. O., Vargas-Cortes M., O'Donnell C. L. Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function. J Exp Med. 1991 May 1;173(5):1053–1063. doi: 10.1084/jem.173.5.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Williamson J. D., Reith R. W., Jeffrey L. J., Arrand J. R., Mackett M. Biological characterization of recombinant vaccinia viruses in mice infected by the respiratory route. J Gen Virol. 1990 Nov;71(Pt 11):2761–2767. doi: 10.1099/0022-1317-71-11-2761. [DOI] [PubMed] [Google Scholar]
  43. Yang H., Welsh R. M. Induction of alloreactive cytotoxic T cells by acute virus infection of mice. J Immunol. 1986 Feb 15;136(4):1186–1193. [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES