The Role of Natural Killer Cells and Interferon in Virus Infections: A Thesis

Abstract

Definitive evidence that natural killer (NK) cells mediate an antiviral effect in vivo was obtained using murine cytomegalovirus (MCMV) as a model system. Adoptive transfer studies using a variety of physical and immunochemical techniques to enrich and deplete NK cell activity showed that the cell population capable of mediating resistance (as assayed by enhanced survival and reduction in spleen virus titers) had the phenotype of an NK cell: a nylon wool nonadherent, asialo GM1 + , NK 1.2 + , ly 5 + , Thy-1 - , Ia - , low-density lymphocyte. Adoptive transfer of IL-2-dependent cloned NK cells (but not T cells) also provided resistance. NK cells did not provide resistance to lymphocytic choriomeningitis virus (LCMV). Selective depletion of NK cell activity by injection of mice with antibody to anti-asialo GM1 lowered resistance to MCMV, mouse hepatitis virus, and vaccinia virus but not to LCMV. NK cell depletion resulted in up to 1000-fold increases in spleen and liver virus titers, correlating with more severe pathology in these organs. NK cells were found to have antiviral effects early (0-3 days) but not late (6-9 days) postinfection. NK cell depletion resulted in markedly increased MCMV-induced suppression of T cell function, which is probably responsible for the delayed clearance of virus seen in these mice. NK cell depletion resulted in increased virus synthesis during persistent MCMV infection, but had no effect on the course of persistent LCMV infection, despite elevated NK cell and interferon (IFN) levels found in these LCMV-infected mice. The reason why NK cells play a role against MCMV but not LCMV infection was not due to differences in NK cells induced by these 2 viruses, but more likely due to target cell susceptibility. IFN pretreatment of MCMV-infected cells failed to protect them against NK cell-mediated lysis, whereas uninfected and LCMV-infected cells were almost totally protected. These IFN-pretreated, LCMV-infected cells were not resistant to cell-mediated lysis in general, as this treatment increased their sensitivity to virus-specific T cell-mediated lysis by 2- to 3-fold. This enhanced sensitivity to lysis correlated with increased surface expression of H-2 antigens, but not viral antigens. In summary, these studies provide compelling evidence that NK cells can mediate antiviral effects in vivo, and provide some insights into their mode of action and consequences of their disfunction.