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. 1995 Dec;102(3):487–495. doi: 10.1111/j.1365-2249.1995.tb03842.x

An immunosuppressive murine leukaemia virus induces a Th1-->Th2 switch and abrogates the IgM antibody response to sheep erythrocytes by suppressing the production of IL-2.

A Faxvaag 1, T Espevik 1, A Dalen 1
PMCID: PMC1553373  PMID: 8536362

Abstract

Many retroviruses have tropism for cells in the immune system and have a propensity to induce immunosuppression in the host. Some of the effects of retroviruses on immune cell function are thought to be mediated through cytokines. Friend ImmunoSuppressive virus-2 (FIS-2) is a low oncogenic murine leukaemia virus (MuLV) that induces lymphadenopathy and immunosuppression in NMRI mice. The role of T cell cytokines during the generation of a primary antibody response in healthy and FIS-2-infected mice was studied following the antibody response to sheep erythrocytes by an in vitro immunization (IVI) technique. In cultures from FIS-2-infected mice, the antibody response was reduced compared with cultures from uninfected mice and the production of the Th2 cytokines IL-4 and IL-6 was elevated, whereas the Th1 cytokines IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were reduced. The suppressed anti-sheep erythrocyte antibody response in cultures from mice infected with FIS-2 seemed to be caused by an insufficient production of IL-2, since addition of recombinant IL-2 stimulated the antibody response. This effect was also observed in cultures depleted of T cells, indicating a direct effect of IL-2 on B cells. A switch to a Th2 cell response and suppression of IL-2 production might play a central role in the immune cell dysfunction induced by FIS-2.

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Selected References

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  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Bendinelli M., Matteucci D., Friedman H. Retrovirus-induced acquired immunodeficiencies. Adv Cancer Res. 1985;45:125–181. doi: 10.1016/s0065-230x(08)60268-7. [DOI] [PubMed] [Google Scholar]
  3. Carter R. L., Chesterman F. C., Rowson K. E., Salaman M. H., Wedderburn N. A new virus of minimal pathogenicity associated with Friend virus. II. Histological changes and immunodepressive effect. Int J Cancer. 1970 Jan 15;5(1):103–110. doi: 10.1002/ijc.2910050114. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Cianciolo G. J., Kipnis R. J., Snyderman R. Similarity between p15E of murine and feline leukaemia viruses and p21 of HTLV. Nature. 1984 Oct 11;311(5986):515–515. doi: 10.1038/311515a0. [DOI] [PubMed] [Google Scholar]
  6. Clerici M., Giorgi J. V., Chou C. C., Gudeman V. K., Zack J. A., Gupta P., Ho H. N., Nishanian P. G., Berzofsky J. A., Shearer G. M. Cell-mediated immune response to human immunodeficiency virus (HIV) type 1 in seronegative homosexual men with recent sexual exposure to HIV-1. J Infect Dis. 1992 Jun;165(6):1012–1019. doi: 10.1093/infdis/165.6.1012. [DOI] [PubMed] [Google Scholar]
  7. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  9. Cunningham A. J., Szenberg A. Further improvements in the plaque technique for detecting single antibody-forming cells. Immunology. 1968 Apr;14(4):599–600. [PMC free article] [PubMed] [Google Scholar]
  10. Dai H. Y., Faxvaag A., Troseth G. I., Aarset H., Dalen A. Molecular cloning and characterization of an immunosuppressive and weakly oncogenic variant of Friend murine leukemia virus, FIS-2. J Virol. 1994 Nov;68(11):6976–6984. doi: 10.1128/jvi.68.11.6976-6984.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dent P. B. Immunodepression by oncogenic viruses. Prog Med Virol. 1972;14:1–35. [PubMed] [Google Scholar]
  12. Dracott B. N., Wedderburn N., Doenhoff M. J. The immunodepressive effect of Friend virus III. Effects on spleen T cells. Immunology. 1977 Oct;33(4):573–580. [PMC free article] [PubMed] [Google Scholar]
  13. Edelman A. S., Zolla-Pazner S. AIDS: a syndrome of immune dysregulation, dysfunction, and deficiency. FASEB J. 1989 Jan;3(1):22–30. doi: 10.1096/fasebj.3.1.2562947. [DOI] [PubMed] [Google Scholar]
  14. Espevik T., Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods. 1986 Dec 4;95(1):99–105. doi: 10.1016/0022-1759(86)90322-4. [DOI] [PubMed] [Google Scholar]
  15. Espevik T., Waage A., Faxvaag A., Shalaby M. R. Regulation of interleukin-2 and interleukin-6 production from T-cells: involvement of interleukin-1 beta and transforming growth factor-beta. Cell Immunol. 1990 Mar;126(1):47–56. doi: 10.1016/0008-8749(90)90299-7. [DOI] [PubMed] [Google Scholar]
  16. Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
  17. Faxvaag A., Dai H. Y., Aarseth H., Dalen A. B. A low oncogenic variant of Friend murine leukemia virus with strong immunosuppressive properties. Arch Virol. 1993;131(3-4):265–275. doi: 10.1007/BF01378631. [DOI] [PubMed] [Google Scholar]
  18. Faxvaag A., Espevik T., Dalen A. Multiple derangements of cytokine homeostasis in mice infected with immunosuppressive retrovirus. Cell Immunol. 1993 Sep;150(2):247–256. doi: 10.1006/cimm.1993.1194. [DOI] [PubMed] [Google Scholar]
  19. Faxvaag A., Moen T., Dalen A. B. Polyclonal activation of B-lymphocytes and induction of autoimmunity in retrovirus infected NMRI mice. Scand J Immunol. 1993 Nov;38(5):459–462. doi: 10.1111/j.1365-3083.1993.tb02588.x. [DOI] [PubMed] [Google Scholar]
  20. Fernandez-Botran R., Krammer P. H., Diamantstein T., Uhr J. W., Vitetta E. S. B cell-stimulatory factor 1 (BSF-1) promotes growth of helper T cell lines. J Exp Med. 1986 Aug 1;164(2):580–593. doi: 10.1084/jem.164.2.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gazzinelli R. T., Makino M., Chattopadhyay S. K., Snapper C. M., Sher A., Hügin A. W., Morse H. C., 3rd CD4+ subset regulation in viral infection. Preferential activation of Th2 cells during progression of retrovirus-induced immunodeficiency in mice. J Immunol. 1992 Jan 1;148(1):182–188. [PubMed] [Google Scholar]
  22. Germann T., Gately M. K., Schoenhaut D. S., Lohoff M., Mattner F., Fischer S., Jin S. C., Schmitt E., Rüde E. Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. Eur J Immunol. 1993 Aug;23(8):1762–1770. doi: 10.1002/eji.1830230805. [DOI] [PubMed] [Google Scholar]
  23. Goff S., Traktman P., Baltimore D. Isolation and properties of Moloney murine leukemia virus mutants: use of a rapid assay for release of virion reverse transcriptase. J Virol. 1981 Apr;38(1):239–248. doi: 10.1128/jvi.38.1.239-248.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  25. Hu-Li J., Ohara J., Watson C., Tsang W., Paul W. E. Derivation of a T cell line that is highly responsive to IL-4 and IL-2 (CT.4R) and of an IL-2 hyporesponsive mutant of that line (CT.4S). J Immunol. 1989 Feb 1;142(3):800–807. [PubMed] [Google Scholar]
  26. Hu-Li J., Shevach E. M., Mizuguchi J., Ohara J., Mosmann T., Paul W. E. B cell stimulatory factor 1 (interleukin 4) is a potent costimulant for normal resting T lymphocytes. J Exp Med. 1987 Jan 1;165(1):157–172. doi: 10.1084/jem.165.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Klinken S. P., Fredrickson T. N., Hartley J. W., Yetter R. A., Morse H. C., 3rd Evolution of B cell lineage lymphomas in mice with a retrovirus-induced immunodeficiency syndrome, MAIDS. J Immunol. 1988 Feb 15;140(4):1123–1131. [PubMed] [Google Scholar]
  28. Lopez-Cepero M., Specter S., Matteucci D., Friedman H., Bendinelli M. Altered interleukin production during Friend leukemia virus infection. Proc Soc Exp Biol Med. 1988 Jul;188(3):353–363. doi: 10.3181/00379727-188-42746. [DOI] [PubMed] [Google Scholar]
  29. Mage M. G., McHugh L. L., Rothstein T. L. Mouse lymphocytes with and without surface immunoglobulin: preparative scale separation in polystyrene tissue culture dishes coated with specifically purified anti-immunoglobulin. J Immunol Methods. 1977;15(1):47–56. doi: 10.1016/0022-1759(77)90016-3. [DOI] [PubMed] [Google Scholar]
  30. Mond J. J., Farrar J., Paul W. E., Fuller-Farrar J., Schaefer M., Howard M. T cell dependence and factor reconstitution of in vitro antibody responses to TNP-B. Abortus and TNP-Ficoll: restoration of depleted responses with chromatographed fractions of a T cell-derived factor. J Immunol. 1983 Aug;131(2):633–637. [PubMed] [Google Scholar]
  31. Morgan D. A., Ruscetti F. W., Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10;193(4257):1007–1008. doi: 10.1126/science.181845. [DOI] [PubMed] [Google Scholar]
  32. Mosier D. E., Yetter R. A., Morse H. C., 3rd Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice. J Exp Med. 1985 Apr 1;161(4):766–784. doi: 10.1084/jem.161.4.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. 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]
  35. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  36. Pattengale P. K., Taylor C. R., Twomey P., Hill S., Jonasson J., Beardsley T., Haas M. Immunopathology of B-cell lymphomas induced in C57BL/6 mice by dualtropic murine leukemia virus (MuLV). Am J Pathol. 1982 Jun;107(3):362–377. [PMC free article] [PubMed] [Google Scholar]
  37. Robinson H. L., Pearson M. N., DeSimone D. W., Tsichlis P. N., Coffin J. M. Subgroup-E avian-leukosis-virus-associated disease in chickens. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 2):1133–1141. doi: 10.1101/sqb.1980.044.01.122. [DOI] [PubMed] [Google Scholar]
  38. Romagnani S. Induction of TH1 and TH2 responses: a key role for the 'natural' immune response? Immunol Today. 1992 Oct;13(10):379–381. doi: 10.1016/0167-5699(92)90083-J. [DOI] [PubMed] [Google Scholar]
  39. Romagnani S., Maggi E., Del Prete G. An alternative view of the Th1/Th2 switch hypothesis in HIV infection. AIDS Res Hum Retroviruses. 1994 May;10(5):iii–ix. doi: 10.1089/aid.1994.10.iii. [DOI] [PubMed] [Google Scholar]
  40. Scheurich P., Thoma B., Ucer U., Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol. 1987 Mar 15;138(6):1786–1790. [PubMed] [Google Scholar]
  41. Schimpl A., Wecker E. Inhibition of in vitro immune response by treatment of spleen cell suspensions with anti-theta serum. Nature. 1970 Jun 27;226(5252):1258–1259. doi: 10.1038/2261258a0. [DOI] [PubMed] [Google Scholar]
  42. Schmitt E., Hoehn P., Germann T., Rüde E. Differential effects of interleukin-12 on the development of naive mouse CD4+ T cells. Eur J Immunol. 1994 Feb;24(2):343–347. doi: 10.1002/eji.1830240211. [DOI] [PubMed] [Google Scholar]
  43. Schumacher J. H., O'Garra A., Shrader B., van Kimmenade A., Bond M. W., Mosmann T. R., Coffman R. L. The characterization of four monoclonal antibodies specific for mouse IL-5 and development of mouse and human IL-5 enzyme-linked immunosorbent. J Immunol. 1988 Sep 1;141(5):1576–1581. [PubMed] [Google Scholar]
  44. Shalaby M. R., Waage A., Espevik T. Cytokine regulation of interleukin 6 production by human endothelial cells. Cell Immunol. 1989 Jul;121(2):372–382. doi: 10.1016/0008-8749(89)90036-1. [DOI] [PubMed] [Google Scholar]
  45. Soldaini E., Matteucci D., Lopez-Cepero M., Specter S., Friedman H., Bendinelli M. Friend leukemia complex infection of mice as an experimental model for AIDS studies. Vet Immunol Immunopathol. 1989 May;21(1):97–110. doi: 10.1016/0165-2427(89)90133-5. [DOI] [PubMed] [Google Scholar]
  46. Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
  47. Tambourin P. E., Wendling F., Jasmin C., Smadja-Joffe F. The physiopathology of Friend leukemia. Leuk Res. 1979;3(3):117–129. doi: 10.1016/0145-2126(79)90009-2. [DOI] [PubMed] [Google Scholar]
  48. Wedderburn N., Salaman M. H. The immunodepressive effect of Friend virus. II. Reduction of splenic haemolysin-producing cells in primary and secondary responses. Immunology. 1968 Sep;15(3):439–454. [PMC free article] [PubMed] [Google Scholar]
  49. Wynn T. A., Eltoum I., Oswald I. P., Cheever A. W., Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. doi: 10.1084/jem.179.5.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zubler R. H., Lowenthal J. W., Erard F., Hashimoto N., Devos R., MacDonald H. R. Activated B cells express receptors for, and proliferate in response to, pure interleukin 2. J Exp Med. 1984 Oct 1;160(4):1170–1183. doi: 10.1084/jem.160.4.1170. [DOI] [PMC free article] [PubMed] [Google Scholar]

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