NK Cells as Viral Responders
NK cells are cytotoxic lymphocytes that directly target infected, stressed, or transformed cells and play a critical role in bridging the innate and the adaptive immune responses (62). In humans, mature NK cells comprise 10–15% of total peripheral blood leukocytes and are described phenotypically as CD3− CD14− CD19− CD56+ CD16+/− (63). NK cells do not undergo clonal selection but instead express several germline-encoded receptors that regulate their activity (62, 64, 65). Upon viral infection, host cells become more susceptible to NK cell killing through: (i) upregulation of self-encoded molecules induced by infection/cellular stress (66, 67) that bind activating NK cell receptors such as Natural Cytotoxicity Receptors (NCRs) (NKp30, NKp44, and NKp46) (68), C-type lectin-like receptors NKG2D and NKp80 (69), and co-activating receptors such as DNAM-1 (70); (ii) downregulation of ligands for inhibitory receptors such as Killer Immunoglobulin-like Receptors (KIRs) (71–73) and the C-type lectin-like receptor CD94-NKG2A (74, 75) which suppress NK cell activation, and; (iii) direct recognition of viral moieties, via engagement of PAMPS (76) or transmembrane activating receptors such as mouse Ly49H (77) or human NKG2C (78). Moreover, NK cells can eliminate virus-infected cells via CD16-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), which has been shown to be particularly important for herpesvirus clearance (79). Finally, NK cell activity is modulated by cytokines, including, but not limited to, the activating cytokines interleukin (IL)-2/12/15/18 (80) and type I IFN, which can be produced by virally infected cells or activated antigen presenting cells (81, 82). IL-2/12/15/18, alone or in combination, promotes NK cell survival, proliferation, cytotoxicity, and cytokine production, including IFN-γ (80). Therefore, NK cells are uniquely equipped to sense and quickly respond to viral infections.