Most lymphocytes participate in adaptive immune responses. These cells, the T and B cells, are responsible for cell-mediated and antibody-mediated immunity, respectively (Chapters 18 and 15). There is, however, a third major population of lymphocytes called natural killer (or NK) cells. NK cells constitute an important subsystem engaged in innate immunity. As such they serve as a first line of defense against pathogens such as viruses, some bacteria, and parasites. They eliminate stressed or damaged cells and play a major role in immunity to tumors.

Natural Killer Cells

Morphology

In most mammals, NK cells are large, granular, nonphagocytic lymphocytes (Figure 19-1). In cattle, NK cells are large cells, although they may not contain large intracytoplasmic granules. There is debate about NK cell morphology in the pig. Some investigators claim that they are large granular lymphocytes, whereas others believe that they are small lymphocytes without obvious cytoplasmic granules (Box 19-1).

Box 19-1   Natural Killer Dendritic Cells

A subset of dendritic cells in humans and mice is cytotoxic. They carry the NK cell marker NK1.1 as well as the dendritic cell marker CD11c. They are found in the spleen, liver, lymph nodes, and thymus of normal mice. Their activity is induced by interferons, LPS, and signals through TLR7, TLR8, and TLR9. They can kill apoptotic and tumor cells but also present antigens to naïve, antigen-specific T cells. They produce copious amounts of IFN-γ on stimulation with CpG nucleotides. These cells may play a key role in linking innate and adaptive immunity. They may be important in killing senescent cells in tissues.

Origins and Location

NK cells develop from bone marrow stem cells. NK cells are distributed widely throughout both lymphoid and nonlymphoid tissues. They are found in peripheral blood, lymph nodes, spleen, and bone marrow. NK cells are not found in the thymus. They range from 2% of the lymphocytes in mouse spleen to 15% in human blood.

Target Cell Recognition

NK cells recognize and kill abnormal cells using totally different mechanisms than do T or B cells. T and B cells use a strategy requiring the recognition of new and foreign antigens. NK cells, in contrast, employ two distinct strategies. One is a “missing-self” strategy. MHC class I molecules expressed on the surface of healthy normal cells can block NK cell killing by sending inhibitory signals. Thus normal cells are not killed. If, however, even a single MHC class I allele is missing, these inhibitory signals are no longer generated, and the target cells are killed. Viruses may suppress MHC class I expression in an attempt to hide from cytotoxic T cells, and tumor cells often fail to express MHC class I. Such cells are prime targets for NK cell attack. Their second strategy involves the use of activating receptors that can recognize that cells are in distress by the presence of stress-induced proteins on their surfaces. By binding to these proteins, NK cells receive signals that cause them to kill their targets (Figure 19-2).

There are three families of these NK cell receptors: the killer cell immunoglobulin (Ig)-like receptor (KIR or CD158) proteins classically expressed in primates, two families of C-type lectin receptors—Ly49 primarily expressed in rodents, and NKG2D receptors expressed in both rodents and primates. All three receptor families contain both inhibitory and activating receptors (Figure 19-3).

NK cells also express CD2, CD16 (FcγRIII), CD178 (CD95L or Fas ligand), CD40L (CD154), toll-like receptors (TLR3 and TLR9), and leukocyte function-associated antigen-1 (LFA-1) (Figure 19-4). NK cells do not express conventional rearranged V-region antigen receptors such as the B cell antigen receptors (BCRs) or T cell antigen receptors (TCRs), nor do they express a CD3 complex.

Receptors

KIR receptors

In humans, the major NK cell MHC class I receptors belong to a multigene family of highly polymorphic proteins called killer cell Ig-like receptor (KIR or CD158) proteins. These are type I transmembrane proteins with two or three extracellular Ig-like domains encoded by a cluster of genes located within the leukocyte receptor gene complex. Through binding to inhibitory KIR receptors, certain MHC class I molecules can protect healthy cells from destruction by NK cells. Other KIR receptors have an opposite effect and stimulate the activity of NK cells. Thus, KIR molecules play a central role in controlling the NK cell response.

The KIR gene locus shows extreme structural diversity as a result of the use of multiple alleles. Allelic polymorphism is so extensive that unrelated individuals with identical KIR haplotypes are very rare. The variations in KIR gene sequences occur at positions that influence their interaction with their MHC class I ligands and as a result influence MHC allelic specificity. These variations tend to occur throughout the gene, unlike the pattern observed in MHC class I and II genes, in which nucleotide variation is restricted to one or two exons. KIR gene expression patterns also vary clonally, so NK cell subsets express random combinations of KIR receptors. This extreme diversity at the KIR locus may be the result of selection pressure, in a manner analogous to that seen in MHC loci. Thus, disease resistance conferred by the KIR locus will vary depending on an animal’s haplotype.

Although human KIR loci vary in their number and diversity, four are present in virtually all haplotypes and are called framework loci. The number of KIR genes expressed by a single individual ranges between 7 and 12, depending on the presence or absence of activating KIR loci. Other members of the KIR protein family include the leukocyte immunoglobulin-like receptors (LILRs) and NKp46 (CD335). NKp46 is only expressed on NK cells. The LILRs are expressed on other types of leukocytes. The KIR and LILR families include not only cellular activating receptors but also inhibitors and receptors with no known ligand.

The distinct binding affinities of activating compared with inhibitory KIR may also contribute to the dominance of inhibition. NK cells become activated when inhibition is removed, so activation must involve stimulatory receptors. Stimulatory KIR probably mediate NK cell activity through recognition of MHC ligands, but little direct binding of activating KIR molecules to these ligands has been detected.

Ly49 Receptors

In rodents and horses, in contrast to humans and cattle, the predominant NK cell MHC class I receptors belong to the Ly49 family. There are at least 23 members (Ly49A to Ly49W) of this family. They are homodimeric type II transmembrane proteins belonging to the C-type lectin family and are functionally equivalent to primate KIRs. The Ly49 molecules are encoded by genes located within the natural killer receptor gene complex. Ly49 haplotypes also contain variable numbers of inhibitory and stimulatory genes, some of which can recognize MHC class I molecules. Ly49 molecules also show specificity for specific MHC alleles. Genomes of humans and other primates contain a single Ly49-like gene. This is a pseudogene in humans, gorilla, and chimpanzee but may be functional in cow, baboon, and orangutan. NK1.1 is another member of the Ly49 family that serves as an activation receptor on mouse NK cells.

NKG2 receptors

The third family of MHC-binding receptors on NK cells are activating molecules belong to the NKG2 receptor system. The NKG2 proteins are also C-type lectins. NKG2D, found on all NK cells, recognizes nonclassical MHC class I proteins produced by stressed cells. Two of the most important of these ligands are polymorphic MHC class I–like molecules called MICA (major histocompatibility complex, class I chain-related A) and MICB coded for by MHC class Ic genes (Chapter 11). Unlike normal class I molecules, these are not associated with antigenic peptides. In addition, they have limited tissue distribution and are minimally expressed on normal, healthy cells but are expressed in large amounts on stressed cells. Stresses may include DNA damage due to ionizing radiation or alkylating agents, heat shock, and oxidative stress (see Figure 19-2). MICA and MICB are especially overexpressed in tumor cells and virus-infected cells. When these ligands are engaged, NKG2D overrides the inhibitory effects of conventional MHC class I molecules and triggers NK cytotoxicity. NKG2D is also expressed on activated γ/δ and α/β T cells, suggesting that they too may have a role in innate immunity. It may be that on surfaces, the combination of γ/δ T cells and NK cells kills tumors, whereas within the body, a combination of α/β T cells and NK cells is most effective.

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