**3. Dictation of natural killer cell function**

NK cells effector functions is a matter of convoluted balance between activating and inhibitory receptors previously explained. The unique feature of those cells to recognize their targets without prior activation has perplexed researchers along the way since early 1990s. NK cells checks for the presence of MHC class I expression that are only present on normal "self" cells just like checking for an ID, and to consider everything lacking this "self" as foreign, which is the case in transformed or virally infected cells; this was first explained by Kärre and colleagues postulating the "missing self" hypothesis [64]. Recognition of the MHC class I molecules is achieved via the inhibitory receptors of NK cells that include members of the killer cell Ig-like receptors (i.e., KIR) [65], in addition to a CD94/NKG2A heterodimer [66].

Upon activation of such inhibitory receptors recruitment of the protein tyrosine phosphatases SHP-1 or SHP-2 was reported which bring about the inhibition of the NK cell activity [67]. Presence of the MHC class I molecules on a given target cell normally will "turn off" the activity of NK cells. However, absence of these molecules was not enough to "turn on" their activity. Instead an activation signal is required, that is mediated by several activating receptors such as natural cytotoxicity receptors (NCRs) that include NKp30, NKp46, and NKp44 as well as the activating receptor NKG2D [68]. Nevertheless, it was reported that NK cell activation mediated by these receptors was tightly controlled by inhibitory receptors as well. Consequently, state of NK cell activation is reached by a balance between the turn on/ turn off signals.

In normal cells, both activating and inhibitory receptors are cross-linked to their ligands but the inhibitory signals received will be able to counteract the activating signals protecting the normal cell from the NK cell cytotoxic effect. On the other hand, this balance was reported to be disrupted in transformed cells, due to a downregulation of the inhibitory ligands and/ or an upregulation of the stress-induced activating ligands, yielding them susceptible to NK cell-mediated killing [69].
