Function and Regulation of Natural Killer (NK) Cells during Viral Infections: Characterization of Responses in Vivo

Although in vitro systems have provided important information about the composition and nature of various immune responses, understanding physiologically relevant function and regulation requires evaluating in vivo conditions. Two different models of acute viral infections have made possible the characterization of a variety of responses to these agents, including natural killer (NK) cell activation and regulation during infection; these are mouse infections with lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). The results of our characterization of the NK cell responses elicited in these models and the methods used to dissect the regulation of these responses are reviewed here. Cytotoxicity, proliferation, and cytokine expression assays as well as flow cytometric analyses are used to characterize the in vivo responses. Both of the infections induce early NK cell cytotoxicity and blastogenesis. Infection with MCMV but not LCMV also induces NK cell production of the antiviral cytokine, interferon-gamma (IFN-gamma). Antibodies, to mediate in vivo cell subset depletion or cytokine neutralization, and mice, genetically altered to have cell subset or cytokine deficiencies, are utilized to identify the regulatory pathways and mechanisms controlling endogenous NK cell responses to the infections. The major mediators of the regulation of NK cell function during viral infection of normal mice are IFN-alpha/beta and interleukin-12 but not interleukin-2. Furthermore, the induction of later T-cell responses contributes to the negative regulation of NK cells by promoting the production of inhibitory factors including biologically active transforming growth factors-beta. Thus, the study of immune responses to viral infections has provided and will continue to provide important insights into the characteristics of endogenous NK cell responses and the cells and factors that regulate these responses in vivo.