Inhibitory receptors that recognize MHC class I molecules function to prevent NK cells from killing normal host cells. The greater the number of MHC class I molecules on a cell surface, the better protected that cell is against attack by NK cells. Interferons induce expression of MHC class I molecules, and protect uninfected host cells from being killed by NK cells, while also activating NK cells to kill virus-infected cells. Viruses and some other intracellular pathogens can cause downregulation of MHC class I molecules as a strategy to prevent the display of antigens as peptides to T cells, also discussed in Chapter 6. NK cells are able to sense this reduction in expression of MHC class I molecules through reduced signaling from their inhibitory receptors. Reduction in MHC class I expression is an example of ‘missing self,’ and increases the chance that an NK cell will kill the target cell. It is thought that the balance of signals from ‘stress-induced self’ and ‘missing self’ determines whether an individual NK cell will be triggered to kill a particular target cell (Fig. 3.39). Thus receptors expressed on NK cells integrate the signals from two types of
Fig. 3.39 Killing by NK cells depends on the balance between activating and inhibitory signals. NK cells have several different activating receptors that signal the NK to kill the bound cell. However, NK cells are prevented from a wholesale attack by another set of inhibitory receptors that recognize MHC class I molecules (which are present on almost all cell types) and that inhibit killing by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I, such as in cells infected with viruses, many of which specifically inhibit MHC class I expression or alter its conformation so as to avoid recognition by CD8 T cells. NK cells may also kill target cells through their expression of the TNF family member TRAIL, which binds to TNFR members DR4 and DR5 expressed by some types of cells. DR4 and DR5 signal through FADD, an adaptor that activates pro-caspase 8, leading to induction of apoptosis of the target cell.
Fig. 3.40 The genes that encode NK receptors fall into two large families.
The first, the leukocyte receptor complex (LRC), comprises a large cluster of genes encoding a family of proteins composed of immunoglobulin-like domains. These include the killer cell immunoglobulin-like receptors (KIRs) expressed by NK cells, the ILT (immunoglobulin-like transcript) class, and the leukocyte-associated immunoglobulin-like receptor (LAIR) gene families. The sialic acid-binding Ig-like lectins (SIGLECs) and members of the CD66 family are located nearby. In humans, this complex is located on chromosome 19. The second gene cluster is called the NK receptor complex (NKC) and encodes killer cell lectin-like receptors (KLRs), a receptor family that includes the NKG2 proteins and CD94, with which some NKG2 molecules pair to form a functional receptor. This complex is located on human chromosome 12. Some NK receptor genes are found outside these two major gene clusters; for example, the genes for the natural cytotoxicity receptors NKp30 and NKp44 are located within the major histocompatibility complex on chromosome 6. Figure based on data courtesy of J. Trowsdale University of Cambridge.
surface receptors, which together control the NK cell’s cytotoxic activity and cytokine production.
3-26 NK-cell receptors belong to several structural families, the KIRs, KLRs, and NCRs.