Natural Killer (NK) cells are key players of innate immune defense against cancerous or virally infected cells (Vivier et al., 2008, 2011). They can lyse diseased cells directly by secretion of cytolytic granules containing pore-forming perforin and lytic granzymes (Orange, 2008; Voskoboinik et al., 2015) into the synaptic cleft (Cartwright et al., 2014). NK cells also contribute to inflammation more broadly by secreting cytokines including IFN-γ and TNF-α (Fauriat et al., 2010). Their responses are regulated by a variety of germline-encoded activating and inhibitory receptors that serve to elicit a response when appropriate while ensuring tolerance to self. Activating receptor NK group member D (NKG2D) is one of the best-studied NK cell receptors (Molfetta et al., 2016). It recognizes major histocompatibility complex (MHC) class I chain–related protein A (MICA), MICB, or UL16 binding protein (ULBP) 1–6 proteins that are rarely expressed at the surface of healthy cells but are up-regulated on, for example, tumor-transformed or virally infected cells. NK cells also express the Fc receptor CD16 (Fcγ-RIIIa), which can trigger antibody-dependent cellular cytotoxicity (ADCC) against opsonized cells. ADCC is clinically important as one of the mechanisms of therapeutic antibodies. For anti-CD20 mAb rituximab, widely used for treatment of non-Hodgkin’s lymphoma and autoimmune diseases (Edwards et al., 2004; Cheson and Leonard, 2008), for example, the engagement of Fc receptors has been shown to be vital for its activity in vivo (Clynes et al., 2000).

Tumor infiltrating or blood NK cells isolated from patients with chronic diseases such as HIV commonly display very low levels of activating receptors. This has been associated with decreased NK cell cytotoxicity and increased disease severity (Costello et al., 2002; Groh et al., 2002; Coudert et al., 2005; Wiemann et al., 2005; Konjević et al., 2007). Receptor down-regulation is commonly the result of internalization; NKG2D, for example, undergoes clathrin-mediated endocytosis upon the ligation of membrane-bound or soluble ligands (Ogasawara et al., 2003; Cerboni et al., 2009). Internalized NKG2D along with its signaling adaptor DAP10 can contribute to activating signaling though ERK1/2 (Quatrini et al., 2015). However, internalization also leads to lysosomal degradation of NKG2D, which is thought to be an important physiological response for dampening immune responses that might otherwise be excessive and damaging.