The Natural Cytotoxicity Receptors in Health and Disease

Abstract

The Natural Cytotoxicity Receptors (NCRs), NKp46, NKp44, and NKp30, were some of the first human activating Natural Killer (NK) cell receptors involved in the non-MHC-restricted recognition of tumor cells to be cloned over 20 years ago. Since this time many host- and pathogen-encoded ligands have been proposed to bind the NCRs and regulate the cytotoxic and cytokine-secreting functions of tissue NK cells. This diverse set of NCR ligands can manifest on the surface of tumor or virus-infected cells or can be secreted extracellularly, suggesting a remarkable NCR polyfunctionality that regulates the activity of NK cells in different tissue compartments during steady state or inflammation. Moreover, the NCRs can also be expressed by other innate and adaptive immune cell subsets under certain tissue conditions potentially conferring NK recognition programs to these cells. Here we review NCR biology in health and disease with particular reference to how this important class of receptors regulates the functions of tissue NK cells as well as confer NK cell recognition patterns to other innate and adaptive lymphocyte subsets. Finally, we highlight how NCR biology is being harnessed for novel therapeutic interventions particularly for enhanced tumor surveillance.

Keywords: disease association; immunoregulation; natural killer cell; receptors; tissue homeostasis.

Figure 1

Overview of individual NCR domain structures. The domain architecture of the NCRs and TM signaling adaptors encoding ITAM residues (green boxes) are displayed. The NCRs are type I TM proteins expressed on the plasma membrane of immune cells. NKp46 (yellow) has two Ig-like domains, whereas NKp30 (pink) and NKp44 (blue) possess only one Ig-like domain. All NCRs contain either a positively charge arginine (R) or lysine (K) residue in their hydrophobic TM domains that can form a salt bridge with a corresponding aspartate (D) residue in the TM domains of the ITAM adaptors; CD3, FcR, or DAP12, respectively. The cytoplasmic domains of the NCRs do not encode any inherent signaling capacity with the exception of NKp44 that contains a putative ITIM sequence (red) in its cytoplasmic tail and thus maintains potential for inhibitory signaling.

Figure 2

Expression of the NCRs and their Ligands. Schematic representation of the expression of the NCRs on NK cells and the NCR ligands by tumors (green) or pathogens or cells infected with pathogens (light blue). NKp30 and NKp46 are expressed by resting (pink) as well as activated (orange) NK cells, whereas NKp44 is only expressed by NK cells activated with IL-2 or IL-15 (arrow). PCNA, BAT3 and NKp44L are nuclear proteins but the pathways whereby they become expressed on the surface of tumor cells remain to be identified. NKp44L is a splice variant of the Mixed-lineage leukemia 5 (MLL5) protein encoding a C-terminal modification reported to mediate cell-surface expression of NKp44L on tumor cells. Similarly, the pathway whereby vimentin becomes expressed on the surface of M. tuberculosis infected cells also remains to be described.