Role of Natural Killer and Gamma-Delta T cells in West Nile Virus Infection

Wang, Tian; Welte, Thomas

There are also conflicting reports about the functional significance of NK cells in WNV-infected hosts. For example, WNV-infected mouse astrocytes were shown to be resistant to NK cell lysis, which was indicative of a low susceptibility of CNS cells to NK cells during WNV infection [30] . When NK cells were depleted in mice by using an antibody against NK1.1, the mice neither became more susceptible to WNV nor was there an increased morbidity. Furthermore, the Ly49a transgenic strain of mice, which is deficient in circulating NK cells, also showed a susceptibility to WNV similar to that of wild-type mice [31] . Thus, the role of NK cells during in vivo WNV infection remains controversial. There are a few possible reasons to explain this complexity. First, the divergent phenotypic and functional features of NK cells are often influenced by organ-specific factors, including local microenvironment and unique cellular interactions [32] . This has been well documented in several disease models. During coronavirus infection or in autoimmune disease, CNS-specific NK cells provided protection against encephalitis, either by reducing viral replication or inhibiting the activation of autoimmune T cells through killing of activated microglia [33, 34] ; whereas during chronic hepatitis C virus infection, hepatic NK cells were found to inhibit liver fibrosis and tissue regeneration by promoting stellate cell death [35] . Likewise, the CNS-specific NK cells may have distinct functions during in vivo infection other than direct killing of WNV-infected local cells. Interestingly, a recent study [36] showed that NK cells were capable of preventing the spread of WNV infection only to certain mouse tissues, such as the liver, but not the spleen. Additionally, WNV could develop strategies in evasion of NK-cell mediated killing during in vivo infection. NK cell activation is regulated by the balance of activating and inhibitory receptors on its surface. The inhibitory receptors killer cell immunoglobulin-like (KIR) receptors in humans, the lectin-like Ly49 (mouse), and the CD94-NKG2A dimers bind to major histocompatibility complex (MHC) class I molecules. Infection of mouse or human cells with flaviviruses is known to increase the cell-surface expression of MHC class I [37, 38] . In particular, WNV infection upregulates MHC class I expression by enhancing the transport activity of TAP and by NF-B-dependent transcription activation of MHC class I genes [39] [40] [41] . Therefore, WNV may evade NK-cell mediated killing by upregulation of MHC class I on infected cells. Lastly, although the depletion approach has been commonly used to determine the functional role of NK cells during in vivo flavivirus infection [31, 42] , it has been reported that NK cells can't be fully depleted in all WNV-infected tissues [36] .