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. 1997 Jan;71(1):267–275. doi: 10.1128/jvi.71.1.267-275.1997

Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells.

C H Tay 1, R M Welsh 1
PMCID: PMC191047  PMID: 8985346

Abstract

Antiviral mechanisms by which natural killer (NK) cells control murine cytomegalovirus (MCMV) infection in the spleens and livers of C57BL/6 mice were measured, revealing different mechanisms of control in different organs. Three days postinfection, MCMV titers in the spleens of perforin 0/0 mice were higher than in those of perforin +/+ mice, but no elevation of liver titers was found in perforin 0/0 mice. NK cell depletion in MCMV-infected perforin 0/0 mice resulted only in an increase in liver viral titers and not in spleen titers. Depletion of gamma interferon (IFN-gamma) in C57BL/6 mice by injections with monoclonal antibodies to IFN-gamma resulted in an increase of viral titers in the liver but not in the spleen. Analyses using IFN-gamma-receptor-deficient mice, rendered chimeric with C57BL/6 bone marrow cells, indicated that in a recipient environment where IFN-gamma cannot exert its effects, the depletion of NK cells caused an increase in MCMV titers in the spleens but had little effect in the liver. IFN-gamma has the ability to induce a variety of cells to produce nitric oxide, and administrating the nitric oxide synthase inhibitor N(omega)-monomethyl-L-arginine into MCMV-infected C57BL/6 mice resulted in MCMV titer increases in the liver but not in the spleen. Taken together, these data suggest that in C57BL/6 mice, there is a dichotomy in the mechanisms utilized by NK cells in the regulation of MCMV in different organs. In the spleen NK cells exert their effects in a perforin-dependent manner, suggesting a cytotoxic mechanism, while in the liver the production of IFN-gamma by NK cells may be a predominant mechanism in the regulation of MCMV synthesis. These results may explain why the Cmv-lr locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver.

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Selected References

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  1. Bellone G., Valiante N. M., Viale O., Ciccone E., Moretta L., Trinchieri G. Regulation of hematopoiesis in vitro by alloreactive natural killer cell clones. J Exp Med. 1993 Apr 1;177(4):1117–1125. doi: 10.1084/jem.177.4.1117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Biron C. A., Byron K. S., Sullivan J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med. 1989 Jun 29;320(26):1731–1735. doi: 10.1056/NEJM198906293202605. [DOI] [PubMed] [Google Scholar]
  3. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  4. Brutkiewicz R. R., Welsh R. M. Major histocompatibility complex class I antigens and the control of viral infections by natural killer cells. J Virol. 1995 Jul;69(7):3967–3971. doi: 10.1128/jvi.69.7.3967-3971.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bukowski J. F., Warner J. F., Dennert G., Welsh R. M. Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J Exp Med. 1985 Jan 1;161(1):40–52. doi: 10.1084/jem.161.1.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bukowski J. F., Woda B. A., Welsh R. M. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J Virol. 1984 Oct;52(1):119–128. doi: 10.1128/jvi.52.1.119-128.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Guidotti L. G., Ishikawa T., Hobbs M. V., Matzke B., Schreiber R., Chisari F. V. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996 Jan;4(1):25–36. doi: 10.1016/s1074-7613(00)80295-2. [DOI] [PubMed] [Google Scholar]
  8. Harris N., Buller R. M., Karupiah G. Gamma interferon-induced, nitric oxide-mediated inhibition of vaccinia virus replication. J Virol. 1995 Feb;69(2):910–915. doi: 10.1128/jvi.69.2.910-915.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Heise M. T., Virgin H. W., 4th The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. J Virol. 1995 Feb;69(2):904–909. doi: 10.1128/jvi.69.2.904-909.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Huang S., Hendriks W., Althage A., Hemmi S., Bluethmann H., Kamijo R., Vilcek J., Zinkernagel R. M., Aguet M. Immune response in mice that lack the interferon-gamma receptor. Science. 1993 Mar 19;259(5102):1742–1745. doi: 10.1126/science.8456301. [DOI] [PubMed] [Google Scholar]
  11. Jacobs P., Radzioch D., Stevenson M. M. Nitric oxide expression in the spleen, but not in the liver, correlates with resistance to blood-stage malaria in mice. J Immunol. 1995 Dec 1;155(11):5306–5313. [PubMed] [Google Scholar]
  12. 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]
  13. Karupiah G., Fredrickson T. N., Holmes K. L., Khairallah L. H., Buller R. M. Importance of interferons in recovery from mousepox. J Virol. 1993 Jul;67(7):4214–4226. doi: 10.1128/jvi.67.7.4214-4226.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Karupiah G., Xie Q. W., Buller R. M., Nathan C., Duarte C., MacMicking J. D. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 1993 Sep 10;261(5127):1445–1448. doi: 10.1126/science.7690156. [DOI] [PubMed] [Google Scholar]
  15. Koo G. C., Peppard J. R. Establishment of monoclonal anti-Nk-1.1 antibody. Hybridoma. 1984 Fall;3(3):301–303. doi: 10.1089/hyb.1984.3.301. [DOI] [PubMed] [Google Scholar]
  16. Kägi D., Ledermann B., Bürki K., Hengartner H., Zinkernagel R. M. CD8+ T cell-mediated protection against an intracellular bacterium by perforin-dependent cytotoxicity. Eur J Immunol. 1994 Dec;24(12):3068–3072. doi: 10.1002/eji.1830241223. [DOI] [PubMed] [Google Scholar]
  17. Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
  18. Ljunggren H. G., Kärre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 1990 Jul;11(7):237–244. doi: 10.1016/0167-5699(90)90097-s. [DOI] [PubMed] [Google Scholar]
  19. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  20. Natuk R. J., Welsh R. M. Chemotactic effect of human recombinant interleukin 2 on mouse activated large granular lymphocytes. J Immunol. 1987 Oct 15;139(8):2737–2743. [PubMed] [Google Scholar]
  21. Orange J. S., Biron C. A. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol. 1996 Feb 1;156(3):1138–1142. [PubMed] [Google Scholar]
  22. Orange J. S., Wang B., Terhorst C., Biron C. A. Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J Exp Med. 1995 Oct 1;182(4):1045–1056. doi: 10.1084/jem.182.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pavić I., Polić B., Crnković I., Lucin P., Jonjić S., Koszinowski U. H. Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol. 1993 Oct;74(Pt 10):2215–2223. doi: 10.1099/0022-1317-74-10-2215. [DOI] [PubMed] [Google Scholar]
  24. Paya C. V., Kenmotsu N., Schoon R. A., Leibson P. J. Tumor necrosis factor and lymphotoxin secretion by human natural killer cells leads to antiviral cytotoxicity. J Immunol. 1988 Sep 15;141(6):1989–1995. [PubMed] [Google Scholar]
  25. Raulet D. H., Held W. Natural killer cell receptors: the offs and ons of NK cell recognition. Cell. 1995 Sep 8;82(5):697–700. doi: 10.1016/0092-8674(95)90466-2. [DOI] [PubMed] [Google Scholar]
  26. Scalzo A. A., Fitzgerald N. A., Simmons A., La Vista A. B., Shellam G. R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J Exp Med. 1990 May 1;171(5):1469–1483. doi: 10.1084/jem.171.5.1469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Scalzo A. A., Fitzgerald N. A., Wallace C. R., Gibbons A. E., Smart Y. C., Burton R. C., Shellam G. R. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J Immunol. 1992 Jul 15;149(2):581–589. [PubMed] [Google Scholar]
  28. Scalzo A. A., Lyons P. A., Fitzgerald N. A., Forbes C. A., Shellam G. R. The BALB.B6-Cmv1r mouse: a strain congenic for Cmv1 and the NK gene complex. Immunogenetics. 1995;41(2-3):148–151. doi: 10.1007/BF00182328. [DOI] [PubMed] [Google Scholar]
  29. Scalzo A. A., Lyons P. A., Fitzgerald N. A., Forbes C. A., Yokoyama W. M., Shellam G. R. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1. Genomics. 1995 Jun 10;27(3):435–441. doi: 10.1006/geno.1995.1074. [DOI] [PubMed] [Google Scholar]
  30. Scott P., Trinchieri G. The role of natural killer cells in host-parasite interactions. Curr Opin Immunol. 1995 Feb;7(1):34–40. doi: 10.1016/0952-7915(95)80026-3. [DOI] [PubMed] [Google Scholar]
  31. Shellam G. R., Allan J. E., Papadimitriou J. M., Bancroft G. J. Increased susceptibility to cytomegalovirus infection in beige mutant mice. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5104–5108. doi: 10.1073/pnas.78.8.5104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Storkus W. J., Dawson J. R. Target structures involved in natural killing (NK): characteristics, distribution, and candidate molecules. Crit Rev Immunol. 1991;10(5):393–416. [PubMed] [Google Scholar]
  33. Tay C. H., Welsh R. M., Brutkiewicz R. R. NK cell response to viral infections in beta 2-microglobulin-deficient mice. J Immunol. 1995 Jan 15;154(2):780–789. [PubMed] [Google Scholar]
  34. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. doi: 10.1016/S0065-2776(08)60664-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Trinchieri G. Recognition of major histocompatibility complex class I antigens by natural killer cells. J Exp Med. 1994 Aug 1;180(2):417–421. doi: 10.1084/jem.180.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Walsh C. M., Matloubian M., Liu C. C., Ueda R., Kurahara C. G., Christensen J. L., Huang M. T., Young J. D., Ahmed R., Clark W. R. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10854–10858. doi: 10.1073/pnas.91.23.10854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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]
  38. Welsh R. M., O'Donnell C. L., Shultz L. D. Antiviral activity of NK 1.1+ natural killer cells in C57BL/6 scid mice infected with murine cytomegalovirus. Nat Immun. 1994 Sep-Oct;13(5):239–245. [PubMed] [Google Scholar]
  39. Wu B. C., Ho M. Characteristics of infection of B and T lymphocytes from mice after inoculation with cytomegalovirus. Infect Immun. 1979 Jun;24(3):856–864. doi: 10.1128/iai.24.3.856-864.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yokoyama W. M. Natural killer cell receptors. Curr Opin Immunol. 1995 Feb;7(1):110–120. doi: 10.1016/0952-7915(95)80036-0. [DOI] [PubMed] [Google Scholar]
  41. Yokoyama W. M. Recognition structures on natural killer cells. Curr Opin Immunol. 1993 Feb;5(1):67–73. doi: 10.1016/0952-7915(93)90083-5. [DOI] [PubMed] [Google Scholar]
  42. Yokoyama W. M., Seaman W. E. The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu Rev Immunol. 1993;11:613–635. doi: 10.1146/annurev.iy.11.040193.003145. [DOI] [PubMed] [Google Scholar]

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