Trends in Immunology
ReviewActivating natural cytotoxicity receptors of natural killer cells in cancer and infection
Section snippets
NK cells in health and disease
Human NK cells are important innate immune effector cells that provide rapid responses to tumour and infected cells [1]. Their importance is underscored by the fact that patients with NK cell deficiency suffer from severe recurrent systemic and life-threatening infections, in particular by herpes viruses such as human cytomegalovirus (HCMV) [2]. Strikingly, high activity of peripheral blood NK cells is associated with a 10% lower incidence of tumours for men and 4% for women [3], and their
NCRs
The NCRs are type I membrane proteins and belong to the immunoglobulin superfamily 35, 40, 41, 42, 43. All of the NCRs comprise an extracellular ligand-binding domain, which binds to cellular and exogenously derived ligands, a transmembrane domain, and a short cytosolic domain (Figure 1). The NCRs lack a functional intracellular signalling domain and therefore associate with appropriate adaptor proteins via a charged residue in their transmembrane domain [12].
Discovering cellular ligands of the
NCR signalling and signal integration
NCR signaling pathways involve many of the known ITAM-dependent signaling molecules (Figure 1) [16]. These include SRC family kinase, which phosphorylate the ITAMs of NCR adaptor molecules, resulting in recruitment and activation of zeta chain-associated protein kinase 70 (ZAP70) and spleen tyrosine kinase (SYK). These kinases phosphorylate transmembrane adaptor molecules such as linker for the activation of T cells (LAT) and NTAL (non-T cell activation linker) leading to the association,
Tumour mechanisms for evasion from NK cells
Consistent with the observation that NK cells are an important component of antitumour immune responses, several tumour escape strategies to evade the NKG2D-induced NK cell-mediated attack of these cells have been identified (reviewed in 10, 13, 20, 92). By contrast, only a few tumour immune escape mechanisms are known to target the NCR system (Figure 3). This could be due to the fact that most of the known NCR ligands are pathogen derived (Table 1) and knowledge of the molecular nature of
Future directions
Much progress has been made in recent years on the characterisation of receptor–ligand interactions involved in NK cell activation, especially with regard to NKG2D and its ligands. Much less is known about the NCRs; probably because most ligands identified so far are pathogen derived and the identification of cellular ligands of the NCRs remains challenging (Box 1). The NCRs play an important role in NK cell biology. A special emphasis is placed on the NCRs not only because they act as
Concluding remarks
NK cells hold promise for adoptive cancer immunotherapy, however, their use is challenged by immune escape strategies and the requirement of targeted delivery of the effector NK cells [105]. As a proof of concept, engineered clinically applicable human NK-92 cells carrying a chimeric antigen receptor (CD20-specific antibody fragment fused to the CD3ζ chain) have been shown to overcome resistance of lymphoma and leukaemia cells to NK cell-mediated killing [106], indicating that a similar
Acknowledgements
The laboratory of J.K. is supported by institutional funds of the Georg-Speyer-Haus and by grants from LOEWE Center for Cell and Gene Therapy Frankfurt funded by: Hessisches Ministerium für Wissenschaft und Kunst (HMWK) funding reference number: III L 4- 518/17.004 (2010) and the Wilhelm-Sander Stiftung (2010.104.1). The Georg-Speyer-Haus is funded jointly by the German Federal Ministry of Health (BMG) and the Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK).
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2022, Advances in Protein Chemistry and Structural BiologyCitation Excerpt :Unlike other NK cell receptor families that preferentially bind self-MHC and MHC-related ligands, natural cytotoxicity receptors preferentially recognize pathogen-derived molecules and non-MHC self-markers (Hudspeth, Silva-Santos, & Mavilio, 2013). NCRs functions in the immune system, although also described for tumor cytotoxicity, are strongly related to NK cell activation in antiviral and pathogen-derived immune responses (Koch et al., 2013). In addition to their cytotoxicity-promoting activities, NCRs can also mediate the production of proinflammatory cytokines by NK cells, thus promoting pathogen clearance and immune response modulation (Hudspeth et al., 2013).