FIGURE 4-6 Functions of activating and inhibitory receptors of NK cells. A, Activating receptors of NK cells recognize ligands on target cells and activate protein tyrosine kinase (PTK), whose activity is inhibited by inhibitory receptors that recognize class I MHC molecules and activate protein tyrosine phosphatases (PTP). NK cells do not efficiently kill class I MHC-expressing healthy cells. B, If a virus infection or other stress inhibits class I MHC expression on infected cells and induces expression of additional activating ligands, the NK cell inhibitory receptor is not engaged and the activating receptor functions unopposed to trigger responses of NK cells, such as killing of target cells and cytokine secretion. C. Cells stressed by infection or neoplastic transformation may express increased amounts of activating ligands, which bind NK cell activating receptors and induce more tyrosine phosphorylation than can be removed by inhibitory receptor associated phosphatases, resulting in killing of the stressed cells. Structural details and ligands of inhibitory and activating NK cell receptors are shown in Figure 4-7.
infected cells through activating receptors. The net result will be activation of the NK cell to secrete cytokines and to kill the infected or stressed cell. This ability of NK cells to become activated by host cells that lack class I MHC has been called recognition of missing self.
Inhibitory receptors of NK cells share the common feature of a structural motif in their cytoplasmic tails, called an immunoreceptor tyrosine-based inhibition motif (ITIM), which engages molecules that block the signaling pathways of activating receptors (see Figs. 4-6 and 4-7). ITIMs contain tyrosine residues that are phos-phorylated on ligand binding to the inhibitory receptor. This leads to the recruitment and activation of phospha-tases, which remove phosphates from several signaling proteins or lipids generated by the signaling pathways downstream of NK activating receptors. The end result is blocking of the signaling functions of activating receptors. ITIMs are found in cytoplasmic tails of other receptors besides NK inhibitory receptors, and their structure and signaling functions are discussed in more detail in Chapter 7.
The largest group of NK inhibitory receptors are the killer cell immunoglobulin-like receptors (KIRs), which are members of the immunoglobulin (Ig) superfamily. Members of this family all contain a structural domain called an Ig fold, first identified in antibody (also known as Ig) molecules, discussed in Chapter 5. KIRs bind a variety of class I MHC molecules. A second important group of NK inhibitory receptors belong to the C-type lectin family, which includes proteins with carbohydrate-binding properties, as discussed earlier. One of these receptors is a heterodimer called CD94/NKG2A, which
Cytoplasmic signaling subunits
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