Abstract
The importance of natural killer (NK) cells in the early immune response to viral or bacterial infection is well known. However, the phenotype, function, and physiologic role of NK cells during the late stage of persistent viral infection have not been extensively studied. Here, we characterized NK cells in mice persistently infected with lymphocytic choriomeningitis virus clone 13 and showed that in contrast to NK cells from acutely infected or uninfected mice, NK cells from chronically infected mice expressed a terminally differentiated phenotype, stronger cytotoxicity, and reduced inhibitory receptor expression. In an in vivo tumor model, chronically infected mice exhibited significantly delayed tumor progression in an NK cell-dependent manner. NK cells from chronically infected mice also expressed high STAT1, and blocking the type I interferon (IFN) receptor revealed that type I IFN signaling directly regulated NK cell cytotoxicity. Our findings indicate that sustained type I IFN signaling during chronic viral infection potentiates the cytolytic function of NK cells and contributes to NK cell-dependent host immune surveillance.
Highlights
Chronic viral infections, such as those caused by human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus (HCV), are global health problems
Chronic lymphocytic choriomeningitis virus (LCMV) infection results in a decreased population of mature natural killer (NK) cells To investigate the role of NK cells after establishment of chronic viral infection, we used a previously described murine model of chronic, uncontrolled LCMV-clone 13 (Cl13) (Cl13) infection [23]
The frequencies of mature CD27lowCD11bhigh and terminally differentiated CD11bhighKLRG1þ NK cells were higher in Cl13-infected mice than in uninfected or LCMV-Arm–immunized mice (Fig. 1B)
Summary
Chronic viral infections, such as those caused by human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus (HCV), are global health problems. They can lead to a progressive loss of function of the host immune system [1] and an increase in the frequency of opportunistic infections [2]. Coinfection of HIV with persistent GB virus C is associated with delayed HIV disease progression and reduced mortality [3, 4], and mice with latent herpes virus infection have an increased resistance to secondary Listeria monocytogenes or Yersinia pestis infections through chronic. Chronic viral infections can significantly modulate host immune responses to secondary pathogen infections and tumors, the underlying mechanisms for these beneficial effects to the host have yet to be extensively elucidated
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