The activation of NK cells is determined by a balance between engagement of activating and inhibitory

receptors (Fig. 212). The activating receptors recognize cell surface molecules typically expressed on cells infected with
viruses and intracellular bacteria, as well as cells stressed by DNA damage and malignant transformation. Thus, NK cells
eliminate cells infected with intracellular microbes as well as irreparably injured cells and tumor cells. One of the welldefined activating receptors of NK cells is called NKG2D; it recognizes molecules that resemble class I major
histocompatibility complex (MHC) proteins and is expressed in response to many types of cellular stress. Another
activating receptor, called CD16, is specific for immunoglobulin G (IgG) antibodies bound to cells. The recognition of
antibody-coated cells results in killing of these cells, a phenomenon called antibody-dependent cellular
cytotoxicity(ADCC). NK cells are the principal mediators of ADCC. The role of this reaction in antibody-mediated
immunity is described in Chapter 8. Activating receptors on NK cells have signaling subunits that contain
immunoreceptor tyrosine-based activation motifs. (ITAMs) in their cytoplasmic tails. ITAMs, which also are present in
subunits of lymphocyte antigen receptorassociated signaling molecules, become phosphorylated on tyrosine residues
when the receptors recognize their activating ligands. The phosphorylated ITAMs bind and promote the activation of
cytoplasmic protein tyrosine kinases, and these enzymes phosphorylate, and thereby activate, other substrates in several
different downstream signal transduction pathways, eventually leading to cytotoxic granule exocytosis and production of
IFN-.
The inhibitory receptors of NK cells, which block signaling by activating receptors, are specific for self class I MHC
molecules, which are expressed on all healthy nucleated cells. Therefore, class I MHC expression protects healthy cells from
destruction by NK cells. (In Chapter 3 we describe the important function of MHC molecules in displaying peptide antigens
to T lymphocytes.) Two major families of NK cell inhibitory receptors are the killer cell immunoglobulin-like receptors
(KIRs), so called because they share structural homology with Ig molecules (see Chapter 4), and receptors consisting of a
protein called CD94 and a lectin subunit called NKG2. Both families of inhibitory receptors contain in their cytoplasmic
domains structural motifs called immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which become
phosphorylated on tyrosine residues when the receptors bind class I MHC molecules. The phosphorylated ITIMs bind and
promote the activation of cytoplasmic protein tyrosine phosphatases. These phosphatases remove phosphate groups from
the tyrosine residues of various signaling molecules, thereby counteracting the function of the ITAMs and blocking the
activation of NK cells through activating receptors. Therefore, when the inhibitory receptors of NK cells encounter self
MHC molecules on normal host cells, the NK cells are shut off (see Fig. 212). Many viruses have developed mechanisms
to block expression of class I molecules in infected cells, which allows them to evade killing by virus-specific CD8+ CTLs.
When this happens, the NK cell inhibitory receptors are not engaged, and if the virus induces expression of activating
ligands at the same time, the NK cells become activated and eliminate the virus-infected cells.
The role of NK cells and CTLs in defense illustrates how hosts and microbes are engaged in a constant struggle for
survival. The host uses CTLs to recognize MHC-displayed viral antigens, viruses inhibit MHC expression to evade killing
of the infected cells by CTLs, and NK cells can compensate for the defective CTL response because the NK cells are more
effective in the absence of MHC molecules. The winner of this struggle, the host or the microbe, determines the outcome
of the infection. The same principles may apply to the functions of NK cells in eradication of tumors, many of which also
attempt to escape from CTL-mediated killing by reducing expression of class I MHC molecules.