Figure 2
As mentioned, most of the inhibitory signals are triggered by ITIM motifs. Activation signals are transduced by ITAM motifs located in the cytoplasmic portion of the receptor or of associated molecules, that include DAP12. The activating receptor NKG2D, constitutively expressed by all NK cells, bears no ITAM motif. Therefore, in order to transduce stimulatory signals, NKG2D is associated with an adaptor subunit designated DAP10 (Farag, Fehniger, Ruggeri, Velardi & Caligiuri, 2002). DAP10 does not contain ITAM motifs either, but is able to recruit PI3K activity upon tyrosine phosphorylation of its YINM motif (Lanier, 2009).
NK cells also present receptors that can either activate or inhibit the response, namely the natural cytotoxicity receptors (NCRs) 2B4 and NKR-P1. The 2B4 receptor has been classified as a multi-functional receptor with an activity (activation or inhibition) that depends on the stage of NK cell maturation. Also, two isoforms of this receptor have been identified, with different intracellular domains (an ITIM and an immunoreceptor tyrosine-based switching motif, ITSM), of which only one transduces stimulatory signals. Similarly, the NKR-P1 receptor family contains several members, of which two contain ITIM motifs and one is associated with a high-affinity IgE receptor (FcεRI) that bears ITAM motifs, thus transducing an activation signal.
Tumour cells are generally under a constant state of cellular stress due to hypoxia, chronic proliferative signals, and genome instability. Not surprisingly, cells under these conditions upregulate KAR ligands, becoming susceptible to NK cell killing. Some mutations, characteristic of carcinogenesis, also downregulate the presentation of MHC I molecules, rendering tumour cells more susceptible to attachment by NK cells. To survive, cancer cells develop mechanisms to evade NK cell killing. One of the proposed evasion mechanisms hypothesizes that tumour cells secrete soluble forms of the activating ligands. Certain human tumours can release soluble forms of MICA and MICB (MHC class I polypeptide-related sequence A and B, respectively), the natural activating ligands of NKG2D. As NKG2D-dependent signalling requires dimerization of the ligands, by saturating the tumour environment with monomeric ligands, tumour cells are able to downmodulate NK cell responses (Groh, Wu, Yee & Spies, 2002). On the other hand, it has been suggested that highly specific NKG2D soluble ligands can reverse completely the desensitization of NK cells and increase tumour regression (Deng et al., 2015).
Other direct evasion mechanisms rely on the secretion of immunosuppressive factors such as IL-10 or TGF-β1 (transforming growth factor β1), or upregulation of MHC I molecules to counteract the stimulating signals of activating ligands. Indirect evasion mechanisms require the activation or inhibition of Tregs, killing of dendritic cells, and even the use of monocytes and macrophages as NK cell desensitizers. Monocytes and macrophages can be reprogrammed by tumour-derived signals and start to express inhibitory molecules, such as TGF-β1, inhibiting the activity of the adjacent NK cells (Peng et al., 2017; Sabry & Lowdell, 2013).