Abstract
In addition to their role as effector cells in virus control, natural killer (NK) cells have an immunoregulatory function in shaping the antiviral T-cell response. This function is further pronounced in perforin-deficient mice that show the enhanced NK-cell proliferation and cytokine secretion upon mouse cytomegalovirus (MCMV) infection. Here, we confirmed that stronger activation and maturation of NK cells in perforin-deficient mice correlates with higher MCMV load. To further characterize the immunoregulatory potential of perforin, we compared the response of NK cells that express or do not express perforin using bone-marrow chimeras. Our results demonstrated that the enhanced proliferation and maturation of NK cells in MCMV-infected bone-marrow chimeras is an intrinsic property of perforin-deficient NK cells. Thus, in addition to confirming that NK-cell proliferation is virus load dependent, our data extend this notion demonstrating that perforin plays an intrinsic role as a feedback mechanism in the regulation of NK-cell proliferation during viral infections.
Highlights
Natural killer (NK) cells play a crucial role in the early stage of mouse cytomegalovirus (MCMV) infection; the contribution of NK cells varies among different mouse strains [1]
We found that in addition to virus load-dependent Ly49H+ NK-cell proliferation, perforin has an intrinsic role as a feedback mechanism in the regulation of NK-cell homeostasis during viral infections
In perforin-deficient mice, the virus control by NK cells was essentially abolished, and no difference between WT virus and Δm157 mutant was found in spite of the fact that significantly more NK cells in perforindeficient mice perforin produced IFN-γ, in comparison with WT control mice (Figure 1B)
Summary
Natural killer (NK) cells play a crucial role in the early stage of mouse cytomegalovirus (MCMV) infection; the contribution of NK cells varies among different mouse strains [1]. In C57BL/6 mice, the activating NK-cell receptor Ly49H mediates resistance to MCMV infection, because of the specific binding of virally encoded m157 protein [2, 3]. Mice lacking the Ly49H receptor fail to exert significant virus control by NK cells during the early post-infection (p.i.) days, because of the fact that MCMV expresses immune evasion mechanisms able to avoid or decrease other means of NK-cell engagement [4,5,6]. Perhaps the best evidence for the role of Ly49H/m157 interaction in MCMV control
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