HLA-C; pathogen encoded ligands?

HLA-E; pathogen encoded ligands?

NK cell membrane

FIGURE 4-7 Structure and ligands of activating and inhibitory receptors of NK cells. Examples of inhibitory and activating NK cell receptors and their ligands. CD16 and the natural cytotoxic receptors (NCRs) associate with Z chain homodimers, FceRly homodimers, or Z-FceRly heterodimers. There are multiple different KIRs, with varying ligand specificities.

recognizes a class I MHC molecule called HLA-E. Interestingly, HLA-E displays peptides derived from other class I MHC molecules, so in essence, CD94/NKG2A is a surveillance receptor for several different class I MHC molecules. A third family of NK inhibitory receptors, called the leukocyte Ig-like receptors (LIRs), are also Ig super-family members that bind class I MHC molecules, albeit with lower affinity than the KIRs, and are more highly expressed on B cells than on NK cells.

Activating receptors on NK cells recognize a heterogeneous group of ligands, some of which may be expressed on normal cells and others of which are expressed mainly on cells that have undergone stress, are infected with microbes, or are transformed. The molecular features of the ligands for many of these receptors are not well characterized. The induced expression of ligands on unhealthy cells that bind to activating receptors on NK cells may lead to signals that overwhelm the signals from inhibitory receptors, especially if class I MHC is also reduced or lost on the unhealthy cell (see Fig. 4-6).

Most activating NK receptors share the common feature of a structural motif in their cytoplasmic tails, called an immunoreceptor tyrosine-based activation motif (ITAM), which engages in signaling events that promote target cell killing and cytokine secretion (see Fig. 4-7). In some of these receptors, a single polypeptide chain contains the ITAM as well as the extracellular ligand-binding portion. In other receptors, the ITAMs are in separate polypeptide chains, such as FceRIy, Z, and DAP12, that do not bind ligand but are noncovalently associated with the ligand-binding chain. ITAMs are also found in cytoplasmic tails of other multichain signaling receptors in the immune system, including the antigen receptors on T and B cells. After ligand binding to the NK cell activating receptors, tyrosine residues within the ITAMs become phosphory-lated by cytoplasmic kinases, other protein kinases are recruited to the modified ITAMs and become activated, and these kinases contribute to further signaling by phos-phorylating additional proteins. The structure and signaling functions of ITAMs are discussed in more detail in Chapter 7.

Many of the NK cell activating receptors are members of the C-type lectin or KIR families, which also include inhibitory receptors, as discussed before. Some of the activating receptors appear to bind class I MHC molecules, like the inhibitory receptors, but it is not known how these receptors are preferentially activated by infected or damaged cells. It is also clear that the activating receptors recognize ligands other than classical MHC molecules. One well-studied NK cell activating receptor in the C-type lectin family is NKG2D, which binds class I MHC-like proteins, including MIC-A and MIC-B, that are found on virally infected cells and tumor cells but not normal cells. The NKG2D receptor associates with a signaling subunit named DAP10, which has a signaling motif different from the ITAMs in other activating receptors but also enhances NK cell cytotoxicity against target cells.

Another important activating receptor on NK cells is CD16 (FcyRIIIa), which is a low-affinity receptor for IgG antibodies. Antibody molecules have highly variable antigen-binding ends, and on the opposite end, they have an invariant structure, called the Fc region, that interacts with various other molecules in the immune system. We will describe the structure of antibodies in detail in Chapter 5 but, for now, it is sufficient to know that CD16 binds to the Fc regions of certain types of antibodies called IgG1 or IgG3. CD16 associates with one of three different ITAM-containing signaling proteins (e.g., FceRIy Z, and DAP12 proteins). During an infection, the adaptive immune system produces IgG1 and IgG3 antibodies that specifically bind to the infecting microbes and their antigens on infected cells, and CD16 on NK cells can bind to the Fc parts of these antibodies. As a result, CD16 generates activating signals, through the associated signaling partners, and the NK cells may kill the infected cells that have been coated with antibody molecules. This process is called antibody-dependent cell-mediated cytotoxicity; it is an effector function of adaptive immunity and will be discussed in Chapter 12 when we consider humoral immunity.

The ability of activating receptors to induce functional responses in NK cells is enhanced by cytokines. The major cytokines of the innate immune system that stimulate NK function are IL-12, IL-15, IL-18, and type I interferons (discussed later). Each of these cytokines enhances the cytotoxic activity of NK cells and the amount of the cytokine IFN-y the NK cells secrete. IFN-y has various antimicrobial effects and will be discussed in detail in Chapter 10. In addition, IL-12 and IL-15 are important growth factors for NK cells.

KIR genes are polymorphic, meaning that there are several allelic variants in the human population, and groups of KIR alleles are often inherited together from a single parent. These groups of linked genes are called KIR haplotypes. There are two major KIR haplotypes and some rarer ones. Haplotypes differ in the number of receptors encoded, and some have more or fewer activating receptors than others. Some haplotypes are associated with increased susceptibility to some diseases, including spontaneous abortion and uveitis.

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