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).