Antiviral roles of natural killer (NK) cell subsets were examined in C57BL/6 mice infected with murine cytomegalovirus (MCMV) and other viruses, including lymphocytic choriomeningitis virus (LCMV), vaccinia virus (VV), and mouse hepatitis virus (MHV). Each virus vigorously induced an NK cell infiltrate into the peritoneal cavity and liver, causing some redistributions of NK cell subsets defined by monoclonal antibody (mAb) directed against Ly49A, C/I, D, and G2. Striking results were seen with a mAb (1F8) reactive with the positively signaling molecule Ly49H, present in MCMV-resistant C57BL/6 mice. mAb 1F8 also stains Ly49 C and I, but exclusion of those reactivities with mAb 5E6, which recognizes Ly49 C and I, indicated that Ly49H+ cells infiltrated the peritoneal cavity and liver and were particularly effective at synthesizing interferon γ. Depletion of 1F8+ but not 5E6+ cells in vivo by mAb injections enhanced MCMV titers by 20-1,000-fold in the spleen and approximately fivefold in the liver. Titers of LCMV or VV were not enhanced. These anti-MCMV effects were attributed to prototypical NK1.1+CD3− NK cells and not to NK1.1+CD3+ “NK/T” cells. This is the first evidence that control of a virus infection in vivo is mediated by a distinct NK cell subset.
SummaryThe 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 LCMVinfected 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 GM l 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. They also show that the NK cell responses to infection in terms of activation and proliferation, as well as a portion of the decline in NK cell activity at later stages of infection, occur independently of T or B cells or their products .
Heat shock proteins (hsp's) isolated from murine cancer cells can elicit protective immunity and specific cytotoxic T lymphocytes (CTLs) by channeling tumor-derived peptides bound to hsp's to the major histocompatibility class I antigen presentation pathway. Here we have investigated if hsp70 can be used in a novel peptide vaccine for the induction of protective antiviral immunity and memory CTLs. A CTL epitope from the well-defined lymphocytic choriomeningitis virus (LCMV) system was mixed with recombinant hsp70 in vitro under conditions that optimize peptide binding to hsp70. Mice were immunized with the hsp70–peptide mixture and challenged with LCMV. Virus titers were reduced 10–100-fold in these mice compared to control mice. Immunization with the hsp70–peptide mixture resulted in the development of CTL memory cells that could be reactivated during LCMV infection, and that in a 51Cr-release assay could lyse cells pulsed with the same peptide, but not cells pulsed with another LCMV peptide. These results show that hsp70 can be used with CTL epitopes to induce efficient protective antiviral immunity and the generation of peptide-specific CTLs. The results also demonstrate the usefulness of hsp70 as an alternative to adjuvants and DNA vectors for the delivery of CTL epitopes to antigen-presenting cells.
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