Natural Killer Cells: From Basic Research to Treatments

Abstract

The immune system is classically divided into innate and adaptive. Adaptive immunity can be defined by the presence of cells (i.e., T and B lymphocytes in higher vertebrates) that clonally express a colossal repertoire of receptors (i.e., the T cell and the B cell antigen receptors), the diversity of which results from somatic DNA rearrangements. Besides T and B cells, natural killer (NK) cells have been originally defined as cytolytic lymphocytes that selectively eliminate tumor cells without antigen-specific receptors (Oldham and Herberman, 1973; Herberman et al., 1975; Kiessling et al., 1975). NK cells are lymphocytes of the innate immune system that can kill an array of target cells and secrete cytokines that participate to the shaping of the adaptive immune response (Vivier et al., 2008, 2011). A feature of NK cells resides in their capacity to distinguish stressed cells (such as tumor cells, microbe-infected cells, cells which have undergone physical or chemical injuries) from normal cells via an array of germline-encoded recognition receptors. The acquisition of cell cytotoxicity during evolution has been associated with the development of highly sophisticated and robust mechanisms that control the initiation of the cytolytic processes and avoid tissue damage. Along this line, much progress has been made over the last 15 years in the dissection of the mechanisms that allow NK cells to discriminate target cells from other healthy “self” cells. These data have been instrumental in defining several immune recognition strategies and in the emergence of the “dynamic equilibrium concept.” The NK cell detection system includes a variety of cell surface activating and inhibitory receptors, the engagement of which regulates NK cell activities. Thus, the integration of antagonistic pathways upon interaction with neighboring cells governs the dynamic equilibrium regulating NK cell activation and dictates whether or not NK cells are activated to kill target cells (Moretta and Moretta, 2004; Vivier et al., 2004; Lanier, 2005). Natural killer cells use inhibitory receptors to gauge the absence of constitutively expressed self-molecules on susceptible target cells. In particular, NK cells express MHC class I-specific receptors and “lose” inhibitory signals when encountering MHC class I-deficient hematopoietic cells in several in vitro and in vivo models. As a consequence, NK cells can recognize “missing self” on hematopoietic cells (Kärre et al., 1986; Bix et al., 1991). The MHC class I-specific inhibitory receptors include the killer cell immunoglobulin-like receptors (KIRs) in humans, the lectin-like Ly49 dimers in the mouse and the lectin-like CD94-NKG2A heterodimers in both species (Yokoyama and Plougastel, 2003; Parham, 2005). A conserved feature of these inhibitory receptors resides in the presence of one or two intracytoplasmic inhibitory signaling domains called immunoreceptor tyrosine-based inhibition motifs (ITIMs; Burshtyn et al., 1996; Olcese et al., 1996). By interacting with MHC class I molecules that are constitutively expressed by most healthy cells in steady-state conditions but that may be lost upon stress, inhibitory MHC class I receptors provide a way for NK cells to ensure tolerance to self while allowing toxicity toward stressed cells. MHC class I is not the only constitutive self-signal detected by NK cells, as other inhibitory receptors (for example, mouse NKR-P1B, human NKR-P1A, and mouse 2B4) that recognize non-MHC self-molecules (for example, Clr-b, LLT-1, and CD48, respectively) also regulate NK cell activation (Kumar and McNerney, 2005). MHC class I-specific inhibitory receptors and their ligands (H-2 in mice and HLA in humans) are highly polymorphic molecules encoded by multigenic, multiallelic families of genes that are inherited independently (Yokoyama and Plougastel, 2003; Parham, 2005). NK cells have thus to discriminate self in a context where self-molecules differ from individuals to individuals. Like T lymphocytes, NK cells are educated to self versus altered-self discrimination. This education, also termed “tuning, licensing, or arming” leads to the maturation of a NK cell functional repertoire (i.e., the ensemble of stimulations toward which NK cells are reactive), which is adapted to self-MHC class I environment (Fernandez et al., 2005; Kim et al., 2005; Anfossi et al., 2006; Raulet and Vance, 2006; Yokoyama and Kim, 2006). Consequently, NK cells in MHC class I-deficient hosts are hyporesponsive to stimulatory receptor stimulation and thereby tolerant to self. Other studies have reported that the hyporesponsiveness of NK cells grown in a MHC class I-deficient environment can be overcome by inflammatory conditions in NK cell environment (Tay et al., 1995; Orr et al., 2010). It remains that two types of self-tolerant NK cells coexist in vivo at steady-state: functionally competent NK cells, whose effector responses are inhibited by the recognition of self-MHC class I molecules, and hyporesponsive NK cells that cannot detect self-MHC class I. NK cell education does not result in an on/off switch, but rather in a quantitative tuning of NK cell responsiveness: the more inhibitory receptors recognizing self-MHC class I are expressed, the more NK cells are responsive to cells lacking self-MHC class I (Brodin et al., 2009; Joncker et al., 2009; Hoglund and Brodin, 2010). The molecular mechanisms underlying the MHC-dependent NK cell education have been shown in mice to require a functional ITIM in the intracytoplasmic tail of Ly49 inhibitory receptors (Kim et al., 2005). Recently using spot variable fluorescence correlation spectroscopy to monitor the movement of receptors, we have shown that in NK cells genetically engineered to not be properly educated, inhibitory and activating receptors were confined together in domains where they were associated with an actin network at the plasma membrane...