Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1978 Jul 1;148(1):163–181. doi: 10.1084/jem.148.1.163

Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction

Jr RM Welsh
PMCID: PMC2184910  PMID: 307587

Abstract

Lymphocytic choriomeningitis virus (LCMV) infection of C3H/St, nude (BALB/c background), and other mice induced high levels of natural killer (NK) cell activity in the spleen and peritoneum. L-929 cells were used as targetsand were not lysed by spleen or peritoneal cells from uninfected mice. The cytotoxic cells were characterized as NK cells because they were nonadherent, nonphagocytic lymphocytes lacking θ and immunoglobulin antigens on their plasma membranes. Their activity was sensitive to 6 mM EDTA and to heating for 5 h at 37 degrees C, but resisted treatment with 0.5 percent trypsin. No role for antibody could be demonstrated in these assays. Relative to cytotoxic T-cell activity, the induction of NK cell activity was resistant to X-irradiation of mice with 1,000 rads but was sensitive if mice were first treated with Strontium-89, a bone-seeking isotope. NK cells were induced by LCMV in all tested strains of mice. In C3H/St mice NK cell activity was detected as early as 1 day and peaked at 3 days postinfection. Maximum activity in C3H/St mice was observed in mice 5-10 wk of age, but significant NK activity was also induced in newborns, which subsequently carried virus in their tissues for the duration of their lives. Older LCMV-carriers did not have detectable spleen NK cell activity. No memory oranamnestic response could be demonstrated for NK cell induction. NK cell activity was not induced by LCMV challenge of LCMV-immune mice, but was induced in those mice by infection with Pichinde virus, a closely related virus. The advent of NK cell activity correlated with the synthesis of interferon in LCMV-infected mice. Culture fluids lacking virus infectivity but containing interferon induced cytotoxic cell activity in nude and C3H/St mice. These experiments suggest that LCMV induced NK cells via an interferon-dependent mechanism. When studied in several strains of mice, the continued expression of NK cell activity did not seem to directly correlate with spleen interferon levels, suggesting that additional factors may play a role as well in maintaining the activity of the NK cell in vivo.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Betz S. J., Morrison D. C. Chemical and biologic properties of a protein-rich fraction of bacterial lipopolysaccharides. I. The in vitro murine lymphocyte response. J Immunol. 1977 Oct;119(4):1475–1481. [PubMed] [Google Scholar]
  2. Blanden R. V., Mims C. A. Macrophage activation in mice infected with ectromelia or lymphocytic choriomeningitis viruses. Aust J Exp Biol Med Sci. 1973 Jun;51(3):393–398. doi: 10.1038/icb.1973.35. [DOI] [PubMed] [Google Scholar]
  3. Bro-Jorgensen K., Knudtzon S. Changes in hemopoiesis during the course of acute LCM virus infection in mice. Blood. 1977 Jan;49(1):47–57. [PubMed] [Google Scholar]
  4. Buchmeier M. J., Gee S. R., Rawls W. E. Antigens of Pichinde virus I. Relationship of soluble antigens derived from infected BHK-21 cells to the structural components of the virion. J Virol. 1977 Apr;22(1):175–186. doi: 10.1128/jvi.22.1.175-186.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buchmeier M. J., Oldstone M. B. Virus-induced immune complex disease: identification of specific viral antigens and antibodies deposited in complexes during chronic lymphocytic choriomeningitis virus infection. J Immunol. 1978 Apr;120(4):1297–1304. [PubMed] [Google Scholar]
  6. Cole G. A., Nathanson N., Prendergast R. A. Requirement for theta-bearing cells in lymphocytic choriomeningitis virus-induced central nervous system disease. Nature. 1972 Aug 11;238(5363):335–337. doi: 10.1038/238335a0. [DOI] [PubMed] [Google Scholar]
  7. Dunlop M. B., Doherty P. C., Zinkernagel R. M., Blanden R. V. Secondary cytotoxic cell response to lymphocytic choriomeningitis virus II. Nature and specificity of effector cells. Immunology. 1976 Aug;31(2):181–186. [PMC free article] [PubMed] [Google Scholar]
  8. Haller O., Hansson M., Kiessling R., Wigzell H. Role of non-conventional natural killer cells in resistance against syngeneic tumour cells in vivo. Nature. 1977 Dec 15;270(5638):609–611. doi: 10.1038/270609a0. [DOI] [PubMed] [Google Scholar]
  9. Haller O., Wigzell H. Suppression of natural killer cell activity with radioactive strontium: effector cells are marrow dependent. J Immunol. 1977 Apr;118(4):1503–1506. [PubMed] [Google Scholar]
  10. Herberman R. B., Nunn M. E., Holden H. T., Lavrin D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer. 1975 Aug 15;16(2):230–239. doi: 10.1002/ijc.2910160205. [DOI] [PubMed] [Google Scholar]
  11. Herberman R. B., Nunn M. E., Holden H. T., Staal S., Djeu J. Y. Augmentation of natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic target cells. Int J Cancer. 1977 Apr 15;19(4):555–564. doi: 10.1002/ijc.2910190417. [DOI] [PubMed] [Google Scholar]
  12. Herberman R. B., Nunn M. E., Lavrin D. H., Asofsky R. Effect of antibody to theta antigen on cell-mediated immunity induced in syngeneic mice by murine sarcoma virus. J Natl Cancer Inst. 1973 Nov;51(5):1509–1512. doi: 10.1093/jnci/51.5.1509. [DOI] [PubMed] [Google Scholar]
  13. Herberman R. B., Nunn M. E., Lavrin D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer. 1975 Aug 15;16(2):216–229. doi: 10.1002/ijc.2910160204. [DOI] [PubMed] [Google Scholar]
  14. Jacobs R. P., Cole G. A. Lymphocytic choriomeningitis virus-induced immunosuppression: a virus-induced macrophage defect. J Immunol. 1976 Sep;117(3):1004–1009. [PubMed] [Google Scholar]
  15. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  16. Kiessling R., Hochman P. S., Haller O., Shearer G. M., Wigzell H., Cudkowicz G. Evidence for a similar or common mechanism for natural killer cell activity and resistance to hemopoietic grafts. Eur J Immunol. 1977 Sep;7(9):655–663. doi: 10.1002/eji.1830070915. [DOI] [PubMed] [Google Scholar]
  17. Kiessling R., Klein E., Pross H., Wigzell H. "Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur J Immunol. 1975 Feb;5(2):117–121. doi: 10.1002/eji.1830050209. [DOI] [PubMed] [Google Scholar]
  18. Kiessling R., Klein E., Wigzell H. "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975 Feb;5(2):112–117. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
  19. Kiessling R., Petranyi G., Kärre K., Jondal M., Tracey D., Wigzell H. Killer cells: a functional comparison between natural, immune T-cell and antibody-dependent in vitro systems. J Exp Med. 1976 Apr 1;143(4):772–780. doi: 10.1084/jem.143.4.772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. MIMS C. A. ASPECTS OF THE PATHOGENESIS OF VIRUS DISEASES. Bacteriol Rev. 1964 Mar;28:30–71. doi: 10.1128/br.28.1.30-71.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Macfarlan R. I., Burns W. H., White D. O. Two cytotoxic cells in peritoneal cavity of virus-infected mice: antibody-dependent macrophages and nonspecific killer cells. J Immunol. 1977 Nov;119(5):1569–1574. [PubMed] [Google Scholar]
  22. Nathanson N., Cole G. A. Immunosuppression and experimental virus infection of the nervous system. Adv Virus Res. 1970;16:397–448. doi: 10.1016/S0065-3527(08)60028-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Notkins A. L. Enzymatic and immunologic alterations in mice infected with lactic dehydrogenase virus. Am J Pathol. 1971 Sep;64(3):733–746. [PMC free article] [PubMed] [Google Scholar]
  24. Notkins A. L., Mergenhagen S. E., Howard R. J. Effect of virus infections on the function of the immune system. Annu Rev Microbiol. 1970;24:525–538. doi: 10.1146/annurev.mi.24.100170.002521. [DOI] [PubMed] [Google Scholar]
  25. Perrin L. H., Zinkernagel R. M., Oldstone M. B. Immune response in humans after vaccination with vaccinia virus: generation of a virus-specific cytotoxic activity by human peripheral lymphocytes. J Exp Med. 1977 Oct 1;146(4):949–969. doi: 10.1084/jem.146.4.949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pfizenmaier K., Trostmann H., Röllinghoff M., Wagner H. Cell-mediated immunity in lumphocytic choriomeningitis. I. The specificity of the cytotoxic T lymphocytes. Z Immunitatsforsch Exp Klin Immunol. 1976 Apr;151(3):224–236. [PubMed] [Google Scholar]
  27. Pulkkinen A. J., Pfau C. J. Plaque size heterogeneity: a genetic trait of lymphocytic choriomeningitis virus. Appl Microbiol. 1970 Jul;20(1):123–128. doi: 10.1128/am.20.1.123-128.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rivière Y., Gresser I., Guillon J. C., Tovey M. G. Inhibition by anti-interferon serum of lymphocytic choriomeningitis virus disease in suckling mice. Proc Natl Acad Sci U S A. 1977 May;74(5):2135–2139. doi: 10.1073/pnas.74.5.2135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rodda S. J., White D. O. Cytotoxic macrophages: a rapid nonspecific response to viral infection. J Immunol. 1976 Dec;117(6):2067–2072. [PubMed] [Google Scholar]
  30. Scher I., Ahmed A., Strong D. M., Steinberg A. D., Paul W. E. X-linked B-lymphocyte immune defect in CBA/HN mice. I. Studies of the function and composition of spleen cells. J Exp Med. 1975 Apr 1;141(4):788–803. [PMC free article] [PubMed] [Google Scholar]
  31. Skidmore B. J., Morrison D. C., Chiller J. M., Weigle W. O. Immunologic properties of bacterial lipopolysaccharide (LPS). II. The unresponsiveness of C3H/HeJ Mouse spleen cells to LPS-induced mitogenesis is dependent on the method used to extract LPS. J Exp Med. 1975 Dec 1;142(6):1488–1508. doi: 10.1084/jem.142.6.1488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stobo J. D. Phytohemagglutin and concanavalin A: probes for murine 'T' cell activivation and differentiation. Transplant Rev. 1972;11:60–86. doi: 10.1111/j.1600-065x.1972.tb00046.x. [DOI] [PubMed] [Google Scholar]
  33. Theofilopoulos A. N., Wilson C. B., Bokisch V. A., Dixon F. J. Binding of soluble immune complexes to human lymphoblastoid cells. II. Use of Raji cells to detect circulating immune complexes in animal and human sera. J Exp Med. 1974 Nov 1;140(5):1230–1244. doi: 10.1084/jem.140.5.1230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Unanue E. R. Secretory function of mononuclear phagocytes: a review. Am J Pathol. 1976 May;83(2):396–418. [PMC free article] [PubMed] [Google Scholar]
  35. VOLKERT M., LARSEN J. H., PFAU C. STUDIES ON IMMUNOLOGICAL TOLERANCE TO LCM VIRUS. 4. THE QUESTION OF IMMUNITY IN ADOPTIVELY IMMUNIZED VIRUS CARRIERS. Acta Pathol Microbiol Scand. 1964;61:268–282. doi: 10.1111/apm.1964.61.2.268. [DOI] [PubMed] [Google Scholar]
  36. Vitetta E. S., Artzt K., Bennett D., Boyse E. A., Jacob F. Structural similarities between a product of the T/t-locus isolated from sperm and teratoma cells, and H-2 antigens isolated from splenocytes. Proc Natl Acad Sci U S A. 1975 Aug;72(8):3215–3219. doi: 10.1073/pnas.72.8.3215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. WAGNER R. R. Biological studies of interferon. I. Suppression of cellular infection with eastern equine encephalomyelitis virus. Virology. 1961 Mar;13:323–337. doi: 10.1016/0042-6822(61)90152-0. [DOI] [PubMed] [Google Scholar]
  38. Welsh R. M. Host cell modification of lymphocytic choriomeningitis virus and Newcastle disease virus altering viral inactivation by human complement. J Immunol. 1977 Jan;118(1):348–354. [PubMed] [Google Scholar]
  39. Welsh R. M., Jr, Zinkernagel R. M. Heterospecific cytotoxic cell activity induced during the first three days of acute lymphocytic choriomeningitis virus infection in mice. Nature. 1977 Aug 18;268(5621):646–648. doi: 10.1038/268646a0. [DOI] [PubMed] [Google Scholar]
  40. Welsh R. M., Oldstone M. B. Inhibition of immunologic injury of cultured cells infected with lymphocytic choriomeningitis virus: role of defective interfering virus in regulating viral antigenic expression. J Exp Med. 1977 Jun 1;145(6):1449–1468. doi: 10.1084/jem.145.6.1449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wolfe S. A., Tracey D. E., Henney C. S. Introduction of "natural" killer' cells by BCG. Nature. 1976 Aug 12;262(5569):584–586. doi: 10.1038/262584a0. [DOI] [PubMed] [Google Scholar]
  42. Wong C. Y., Woodruff J. J., Woodruff J. F. Generation of cytotoxic T lymphocytes during coxsackievirus B-3 infection. III. Role of sex. J Immunol. 1977 Aug;119(2):591–597. [PubMed] [Google Scholar]
  43. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]
  44. Zinkernagel R. M., Welsh R. M. H-2 compatibility requirement for virus-specific T cell-mediated effector functions in vivo. I. Specificity of T cells conferring antiviral protection against lymphocytic choriomeningitis virus is associated with H-2K and H-2D. J Immunol. 1976 Nov;117(5 Pt 1):1495–1502. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES