Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 152

and signaling lymphocyte activation molecule (SLAM)-related family member
SLAMF4 [ 279 ]. 157
Integration of signals that emanate from stimulatory and inhibitory receptors
during target cell recognition determines whether NK cells will eliminate their
targets or not. Normal cells display stimulatory ligands, but their MHC class-1
molecules engage inhibitory receptors that counteract stimulatory signaling to avoid
killing.

3.11.5.2 Licensed NK-Cell Receptors

Target cell recognition, a process that is called “licensing”, “arming”, or “education”
leads to full functional maturation of NK cells and promotes the reactivity of mature
NK cells [ 280 ]. Natural killer cells, the inhibitory receptors of which bind to major
histocompatibility complex class-1 molecules are “licensed”, or supposed to be
more responsive to stimulation. On the other hand, “unlicensed” NK cells that lack
receptors for MHC class-1 molecules are assumed to be hyporesponsive [ 281 ].
Stimulatory receptors often recognize self-ligands that are expressed selectively
by transformed, infected, or damaged cells. Inhibitory receptors recognize MHC
class-1 molecules on target cells. Cells that lack MHC class-1 molecules are much
more sensitive to killing primed by NK cells than those with normal amounts of
MHC class-1 molecules [ 280 ].
NK receptors NKG2d target stress-induced self ligands produced by stres-
sed cells (cytomegalovirus UL16-binding protein [ULBP] and MHC class-1 (I)
polypeptide-related sequence molecules [MIC]) [ 282 ]. Other alert molecules in-
clude infectious non-self ligands and Toll-like receptor ligands. A priori, binding
of NKG2a (or KIRc1) and KIR by specific MHC class-1 molecules impedes killing
by NK cells, whereas ligation of activating receptors with corresponding ligands
triggers killing.
In addition, certain inhibitory receptors can bind to their ligands before target cell
encounter, thereby influencing NK-cell responsiveness during subsequent target cell
recognition [ 280 ]. In some circumstances, unlicensed NK cells are more efficient
than licensed cells at eliminating abnormal cells. Therefore, NK cells devoid
of inhibitory receptors for MHC molecules can exert a predominant role [ 280 ].
For example, unlicensed NK cells are the main contributors of the control of
cytomegalovirus infection in mice [ 281 ].

157 The SLAMF4 receptor, a.k.a. natural killer cell receptor NKR2b4 and CD244, is expressed by
all NK cells, γδ T cells, a subset of CD8 + T cells, and all human CD14 + monocytes [ 279 ]. Its
unique ligand is SLAMF2 receptor (or CD48). It operates as either a stimulatory or inhibitory
receptor depending on the expressed isoform that results from alternative splicing.