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

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 .

IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function

“…10 Both NK cells and TLR responses are believed to be important in defense against cytomegalovirus. 17,28 NK cells are valuable in defense against cytomegalovirus, in part because they are capable of recognizing cells with downregulated MHCclass I-a specific evasion mechanism used by the virus. As a result, many human NK cell deficiency states are associated with susceptibility to cytomegalovirus disease.…”

ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells

“…Studies using immunodeficient mice or cell-depleting antibodies have established that NK cells control liver viral load and hepatitis during the first 3 days of MCMV infection (2,(19)(20)(21)(22), a time frame when we observe a significant difference in viral load between WT and ATF3null mice. The ATF3 effect is kinetically compatible with this transcription factor regulating NK cell function.…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…MCMV brain infection of IL-10-deficient mice induces exaggerated chemoattractant CXCL2 production by microglial cells and pathological neutrophil recruitment into the brain. 85 Despite the vital roles that NK cells play during MCMV infection in peripheral organs, [86][87][88] their role in the control of CNS infection has been inadequately studied. 25 In our model of i.p.…”