Natural killer (NK) cells are cytotoxic cells that play important roles in innate immune responses, mainly against viruses and intracellular bacteria. The natural killer designation derives from the fact that their major function is killing infected cells, similar to CD8+ CTLs in the adaptive immune system, but unlike unactivaterd CD8+ T cells, NK cells are functionally competent to kill other cells when they are isolated from the blood or tis sues without further activation (hence natural). NK cells also secrete IFN-γ and thus resemble ILC1s. They are developmentally related to ILC1s but are not considered identical because ILC1s do not have cytotoxic functions. Unlike ILCs, which are found in peripheral tissues but are rare in the blood and lymphoid organs, NK cells constitute 5% to 20% of lymphocytes in the blood and spleen. They are rare in other lymphoid organs and in most non lymphoid tissues, but they are abundant in the liver and placenta. NK cells in the blood appear as large lymphocytes with numerous cytoplasmic granules. NK cells do not express diverse, clonally distributed antigen receptors typical of B and T cells. Rather, they use germline DNA–encoded receptors (discussed later) to distinguish pathogen-infected cells from healthy cells. They can be identified in the blood by the expression of CD56 and the absence of the T-cell marker CD3. Most human blood NK cells also express CD16, an IgG Fc receptor that is involved in the recognition of antibody-coated cells.

Functions of Natural Killer Cells

 The effector functions of NK cells are to kill infected cells and to produce IFN-γ, which activates macrophages to destroy phagocytosed microbes (Fig. 1). The mechanism of NK cell–mediated cytotoxicity is essentially the same as that of CD8+ CTLs, which we will describe in detail in Chapter 11. NK cells, like CTLs, have granules that contain proteins that mediate killing of target cells. When NK cells are activated, granule exocytosis releases these proteins adjacent to the target cells. One NK cell granule protein, called perforin, facilitates the entry of other granule proteins, called granzymes, into the cytosol of target cells. The granzymes are proteolytic enzymes that initiate a sequence of signaling events that cause death of the target cells by apoptosis. By killing cells infected by viruses and intracellular bacteria, NK cells eliminate reservoirs of infection. Early in the course of a viral infection, NK cells are expanded and activated by recognition of activating ligands on the infected cells and by the cytokines IL-12 and IL-15, and they kill infected cells before antigen-specific CTLs can become fully active, which usually takes 5 to 7 days. NK cells may also be important later in the course of viral infection by killing infected cells that have escaped CTL-mediated immune attack by reducing the expression of major histocompatibility complex class I (MHC-I) molecules. Some tumors, especially those of hematopoietic origin, are targets of NK cells because the tumor cells upregulate ligands for activating NK receptors and do not express normal levels or types of MHC-I molecules, which inhibit NK cell activation, discussed later.

Fig1. Functions of natural killer cells. (A) Natural killer (NK) cells recognize ligands on infected cells or cells undergoing other types of stress and kill the host cells. In this way, NK cells eliminate reservoirs of infection as well as dysfunctional cells. (B) NK cells respond to interleukin-12 (IL-12) produced by macrophages and secrete interferon-γ (IFN-γ), which activates the macrophages to kill phagocytosed microbes.

NK cell–derived IFN-γ increases the capacity of macrophages to kill phagocytosed bacteria, similar to IFN-γ produced by T cells. This IFN-γ–dependent NK cell–macrophage interaction can control an infection with intracellular bacteria for several days or weeks and thus allow time for T cell–mediated immunity to develop and eradicate the infection. IFN-γ produced by NK cells in lymph nodes can also direct the differentiation of naive T cells into Th1 cells. Predictably, deficiency of NK cells, seen in rare individuals, leads to increased susceptibility to infection by some viruses and intracellular bacteria.

Activating and Inhibitory Receptors of Natural Killer Cells

NK cells distinguish infected and stressed cells from healthy cells, and NK cell function is regulated by a balance between signals that are generated by activating and inhibitory receptors. In general, the activating receptors recognize ligands on infected and injured cells, and the inhibitory receptors recognize ligands on healthy normal cells (Fig. 2). When an NK cell interacts with another cell, the outcome is determined by the integration of signals generated from the array of inhibitory and activating receptors that are expressed by the NK cell and that interact with ligands on the other cell. Engagement of activating receptors stimulates the killing activity of the NK cells, resulting in destruction of stressed or infected cells. In contrast, engagement of inhibitory receptors blocks signaling by activating ligands, thereby preventing NK destruction of healthy cells. Because of the stochastic nature of their expression, there is significant diversity in the array of activating and inhibitory receptors that different NK cells express in any one individual. Hence, individual NK cells, even in the same person, may respond to cells infected with different types of microbes.

Fig2. Functions of activating and inhibitory receptors of natural killer (NK) cells. (A) Activating receptors of NK cells recognize ligands on target cells and activate protein tyrosine kinases (PTKs), whose activities are inhibited by inhibitory receptors that recognize MHC-I molecules and activate protein tyrosine phosphatases (PTP). NK cells do not efficiently kill MHC-I–expressing healthy cells. (B) If a viral infection or other stress inhibits MHC-I expression on infected cells and induces expression of additional activating ligands, the NK cell inhibitory receptor is not engaged and the activating receptor is unopposed to trigger responses of NK cells, including killing of target cells and cytokine secretion. In addition, infected cells or cancer cells may express increased amounts of activating ligands, inducing more tyrosine phosphorylation than can be removed by inhibitory receptor–associated phosphatases, resulting in killing stressed cells. Structural details and ligands of inhibitory and activating NK cell receptors are shown in Fig3.

Activating receptors on NK cells recognize a heterogeneous group of ligands, some of which may be expressed on normal cells and others mainly on cells that have undergone stress, are infected with microbes, or are neoplastic (see Fig. 3). Many of the NK cell–activating receptors are called killer cell Ig-like receptors (KIRs) because they contain a structural domain named the Ig fold, first identified in antibody (also known as Ig) molecules, dis cussed in Chapter 5. All proteins with Ig folds are members of the Ig superfamily. A second important group of activating NK receptors is similar to the family of C-type lectins, which are proteins with carbohydrate-binding properties similar to the CLRs discussed earlier in the chapter, although these NK receptors do not bind car bohydrates. One well-studied lectin-like NK cell–activating receptor is NKG2D, which binds proteins structurally similar to MHC-I molecules, including MHC-I-related gene A (MIC-A) and MIC-B, and proteins of the ULBP (unique long-16 binding protein) family. The expression of these NKG2D ligands is increased by cellular stress, so they are found on virally infected cells and tumor cells but not normal cells. The NKG2D receptor associates with a subunit named DAP10, which has signaling functions that stimulate NK cell cytotoxicity against target cells.

Fig3. Structure and ligands of activating and inhibitory receptors of natural killer (NK) cells. Different activating and inhibitory receptors of NK cells use different associated signaling components and recognize different ligands. B7-H6 is a member of the B7 family that is expressed mainly on tumor cells. BAT3, HLA-B associated transcript 3; DAP, DNAX-activating protein; HLA, human leukocyte antigen; HSPG, heparan sulfate proteoglycan; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; KIR, killer cell immunoglobulin (Ig)-like receptors; MHC, major histocompatibility complex; MIC, MHC-I polypeptide-related sequence; NCR, natural cytotoxicity receptor; NKG, natural killer group; ULBP, UL-16 binding protein; YxxM, tyrosine-X-X-methionine motif, where X is any amino acid.

Another important activating receptor on NK cells is CD16 (FcγRIIIA), 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 portion, 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 and IgG3. In NK cells, CD16 associates with one of two different signaling proteins (FcεRIγ or ζ). During an infection, the adaptive immune system produces IgG1 and IgG3 antibodies that bind to microbial antigens expressed on the surface of infected cells, and CD16 on NK cells can bind to the Fc regions of these antibodies. As a result, CD16 generates activating signals, through its associated signaling partners, and the NK cells kill the infected cells that have been coated with antibody molecules. This process is called antibody-dependent cell-mediated cytotoxicity; it is an effector mechanism of adaptive immunity, which we will discuss in Chapter 13 when we consider humoral immunity.

Inhibitory receptors of NK cells recognize MHC-I molecules, which are cell surface proteins normally expressed on all healthy nucleated cells in the body (see Fig. 3). A major function of MHC-I molecules, distinct from their role in regulating NK cell activation, is to display peptides derived from cytosolic proteins, including microbial proteins, on the cell surface for recognition by CD8+ T lymphocytes. We will describe the structure and function of MHC molecules in relation to T-cell antigen recognition in Chapter 6. For now, it is important to understand that NK cells use fundamentally different types of receptors than do T cells to recognize MHC-I molecules. These NK receptors for MHC-I molecules inhibit NK cell activation. This is useful because normal cells express MHC-I molecules, but many viruses and other causes of cell stress lead to a loss of cell surface expression of MHC-I. Furthemore, many cancer cells lose expression of MHC-I molecules as a way of escaping from T-cell recognition and killing. Thus, NK cells interpret the presence of MHC-I molecules as a marker of normal, healthy self, and their absence as an indication of infection or damage. As a result, NK cells will be inhibited by healthy cells but will not receive inhibitory signals from infected or stressed cells. At the same time, the NK cells are likely to receive activating signals from infected or damaged cells through activating receptors. The net result is activation of the NK cells to secrete cytokines and to kill the infected or stressed cell. This ability of NK cells to become activated by host cells that lack MHC-I has been called recognition of missing self.

The largest group of NK inhibitory receptors belong to the same KIR family that includes activating receptors, discussed earlier. These inhibitory KIRs bind a variety of different MHC-I molecules. Other inhibitory receptors are lectin-like, such as the CD94/NKG2A heterodimer, which recognizes a non-classical MHC-I molecule called HLA-E. Interestingly, HLA-E displays peptides derived from other MHC-I molecules, so CD94/NKG2A is a surveillance receptor for several different MHC-I molecules.

Activating and inhibitory NK receptors contain structural motifs in their cytoplasmic tails that engage the signaling path ways that respectively promote or inhibit target cell killing and cytokine secretion (see Figs. 2 and 3). Activating receptors have immunoreceptor tyrosine-based activation motifs (ITAMs), which contain tyrosine residues that become phosphorylated by cytoplasmic kinases after binding of ligands to the receptors. Other protein kinases are recruited to the modified ITAMs and become activated, and these kinases contribute to further signaling by phosphorylating and thereby activating enzymatic activities of additional proteins, eventually leading to cytotoxic activity and cytokine secretion. ITAMs are also found in the cytoplasmic tails of other signaling receptors in the immune system, including the antigen receptor complexes of T and B cells, and we will discuss their structure and signaling functions in more detail in Chapter 7. In some activating receptors, a single polypeptide chain contains the cytoplasmic ITAM and the extra cellular ligand-binding portion. In other receptors, the ITAMs are in separate polypeptide chains, such as FcεRIγ (so named because it was first identified as a signaling chain of the Fcε receptor; see Chapter 20), ζ (a component of the TCR complex), and DAP12. These signaling proteins do not bind ligands but are noncovalently associated with the ligand-binding chains (see Fig. 3).

Inhibitory receptors of NK cells have immunoreceptor tyro sine-based inhibition motifs (ITIMs), which engage molecules that block the signaling pathways of activating receptors (see Figs. 2 and 3). ITIMs contain tyrosine residues that are phosphorylated when ligands bind to the inhibitory receptor, and then serve as docking sites for the recruitment and activation of tyrosine phosphatases, which remove phosphates from several signaling proteins generated by the signaling down stream of NK activating receptors. The end result is blocking of the signaling functions of activating receptors. ITIMs are also found in the cytoplasmic tails of other receptors besides NK inhibitory receptors, and we will discuss their structure and signaling functions in more detail in Chapter 7.

KIR genes are polymorphic, meaning that there are several allelic variants in the human population. As a result, one person may express different receptors than another person. Groups of KIR alleles, called KIR haplotypes, are often inherited together from a single parent. There are two major KIR haplotypes and some rarer ones. Haplotypes differ in the number of receptors encoded, such that the number of activating receptors varies among people. Some haplotypes are associated with increased susceptibility to some disorders, including spontaneous abortion and a type of eye inflammation called uveitis.

Cytokines can enhance the functional responses of NK cells. The major cytokines of the innate immune system that stimulate NK cell function are IL-12, IL-15, IL-18, and type I IFNs (discussed later). Each of these cytokines enhances the cytotoxic activity of NK cells, and they can stimulate IFN-γ secretion by the NK cells independent of activating receptors. In addition, IL-15 is an important growth factor for NK cells.

There is emerging evidence that following infections with certain viruses, notably cytomegalovirus (CMV), clones of NK cells proliferate and may develop into long-lived memory-like cells. Thus, NK cell responses may have some features of adaptive immunity. However, the specificity and diversity of these NK cell responses are not established, and neither is their role in defense against such infections.

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مواضيع ذات صلة

Integrins and Integrin Ligands

Selectins and Selectin Ligands

Anatomy and Functions of Lymphoid Tissues : Spleen

Eosinophils

Phagocytosis

Leukocytes (White Blood Cells)

Toll-Like Receptors

Anatomy and Functions of Lymphoid Tissues : Lymph Nodes

Anatomy and Functions of Lymphoid Tissues : Bone Marrow

Populations of Lymphocytes Distinguished by History of Antigen Exposure

Development of Lymphocytes

Dendritic Cells