title: 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.
abstract: The activation, proliferation, and antiviral properties of natural killer (NK) cells were examined in severe combined immunodeficiency (SCID) mice to determine the influence of mature T or B cells on virus-induced NK cell functions and to more conclusively determine the antiviral properties of prototypical CD3- NK cells. NK cells were activated to high levels of cytotoxicity 3 d after infection of mice with lymphocytic choriomeningitis virus (LCMV) or murine cytomegalovirus (MCMV). Analyses of spleen leukocytes from LCMV-infected mice by a variety of techniques indicated that the NK cells proliferated and increased in number during infection. Propidium iodide staining of the DNA of cycling cells revealed that the great majority of proliferating spleen leukocytes 3 d after LCMV infection was of the NK cell phenotype (CD3-, Ig-, Mac-1+, CZ1+, 50% Thy-1+), in contrast to uninfected mice, whose proliferating cells were predominantly of other lineages. Analyses of the NK cell responses over a 2 wk period in control CB17 mice infected with MCMV indicated a sharp rise in serum interferon (IFN) and spleen NK cell activity early (days 3-5) in infection, followed by sharp declines at later stages. In SCID mice the IFN levels continued to rise over a 10-d period, whereas the NK cell response peaked on day 3-5 and gradually tapered. In contrast to the immunocompetent CB17 mice, SCID mice did not clear the MCMV infection and eventually succumbed. SCID mice, again in contrast to immunocompetent CB17 mice, also failed to clear infections with LCMV and Pichinde virus (PV); these mice, infected as adults, did not die but instead developed long-term persistent infections. Depletion of the NK cells in vivo with antiserum to asialo GM1 rendered both SCID and CB17 control mice much more sensitive to MCMV infection, as shown by titers of virus in organs and by survival curves. In contrast, similar depletions of NK cells did not enhance the titers of the NK cell-resistant virus, LCMV. Two variants of PV, one sensitive to NK cells and the other selected for resistance to NK cells by in vivo passage, were also tested in NK cell-depleted SCID mice. The NK-sensitive PV replicated to higher titers in NK cell-depleted SCID mice, whereas the titers of the NK cell-resistant PV were the same, whether or not the mice had NK cells. These experiments support the concept that CD3- prototypical NK cells mediate resistance to NK cell-sensitive viruses via a mechanism independent of antiviral or "natural" antibody.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pathology, University of Massachusetts Medical Center, Worcester 01655.
authors.forename: R M
authors.initials: RM
authors.lastname: Welsh
authors.forename: J O
authors.initials: JO
authors.lastname: Brubaker
authors.forename: M
authors.initials: M
authors.lastname: Vargas-Cortes
authors.forename: C L
authors.initials: CL
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D003587:Cytomegalovirus / Q000302:isolation & purification / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D005434:Flow Cytometry; D007121:Immunocompetence / Q000502:physiology; D007153:Immunologic Deficiency Syndromes / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007694:Killer Cells, Natural / Q000382:microbiology / Q000473:pathology / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000502:physiology; D008216:Lymphocytic Choriomeningitis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008217:Lymphocytic choriomeningitis virus / Q000302:isolation & purification / Q000502:physiology; D008297:Male; D051379:Mice; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology*