Williams Hematology



Identification and Definition of Natural Killer Cells



Origin and Tissue Distribution
Mechanisms of Natural Killer Cell Functions

Cell-Mediated Cytotoxicity

Production of Cytokines
Physiologic Roles of Natural Killer Cells

Natural Resistance

Regulation of Adaptive Immunity

Modulation of Hematopoiesis
Pathologic Alterations in Natural Killer Cell Number and Functions
Chapter References

Natural killer (NK) cells, with a predominant morphology of large granular lymphocytes (LGL), represent a third lineage of lymphoid cells with constitutive ability to mediate cytotoxicity of pathologic target cells and to secrete cytokines. Natural killer cells participate in the innate resistance to intracellular pathogens and malignancies and have a modulatory effect on adaptive immunity as well as hematopoiesis. The activity of NK cells is now known to be regulated by the opposite effects of activating and inhibitory receptors. Malignant expansions of NK cells, either acute or chronic, are rare but represent well-identified clinical entities.

Acronyms and abbreviations that appear in this chapter include: CTL, cytotoxic T lymphocytes; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN, interferon; IL, interleukin; ITIM, immunoreceptor tyrosine-based inhibitory motif; KIR, killer-cell Ig-like receptors; LCMV, lymphocytic choriomeningitis virus; LGL, large granular lymphocytes; M-CSF, macrophage-colony stimulating factor; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor; TNF, tumor necrosis factor.

Natural killer cells were originally identified in the peripheral blood and other lymphoid organs of humans and experimental animals as cells capable of killing a variety of cell types, including tumor-derived cell lines, virus-infected cells, and, in some instances, normal cells in the absence of previous deliberate or known sensitization.1,2 Natural killer cells are currently defined as cytotoxic cells with the predominant morphology of LGL that (1) neither rearrange any of the genes encoding the T-cell receptor (TCR) chains nor express on their surface the CD3 antigen complex or any TCR chain; (2) express on the majority of cells the CD16 (FcgRIIIA) and CD56 (N-CAM) antigens in humans, the NK1.1 antigen in the mouse, and the NKR-PI antigen in the rat; (3) mediate cytolytic reactions even in the absence of MHC class I or class II antigen expression on the target cells. The cytotoxicity mediated by NK cells is clearly distinct from that mediated by cytotoxic T lymphocytes (CTL), which recognize specific antigenic peptides in association with major histocompatibility complex (MHC) class I molecules (see Chap. 84). Cytotoxicity mediated by NK cells is often defined as non-MHC requiring, to distinguish it from the MHC-restricted one mediated by CTL. Certain T lymphocytes that express either an ab or a gd TCR may exhibit, particularly upon activation, TCR-independent cytolytic activity that resembles that of NK cells. These T lymphocytes are appropriately described as displaying NK-like cytotoxicity or non-MHC-requiring cytotoxicity.
Human LGL are medium- to large-sized lymphocytes with round or indented nuclei, condensed chromatin, and usually prominent nucleoli. The cytoplasm is abundant and contains a variety of organelles. Circular membrane-bound granules (primary lysosomes), which are characteristic of these cells, range in diameter from 50 to 800 nm and contain an electron-dense core (internum) surrounded by a layer of lesser opacity (externum). In addition to lysosomal enzymes, the granules contain phospholipids, proteoglycans, and proteins important for cytotoxic lymphocyte function, such as serine esterases (granzymes) and pore-forming proteins (perforins).3,4 Although many NK cells have the morphology typical of LGL,5 a significant proportion of NK cells are indistinguishable from other lymphocytes and may even be agranular.6
Natural killer cells originate in the marrow. Most are short-lived, with life spans calculated to be from a few days to a few weeks.7,8 Natural killer cells derive from the common lymphoid progenitor cell that gives rise to T, B, and NK cells. The cytokine IL-15 plays a particularly important role in the differentiation and expansion of NK cells.9,10 Natural killer cell differentiation does not require the presence of the thymus, although NK cell progenitors can be demonstrated in the thymus, particularly during fetal development.11 The increased number of NK cells and altered anatomical distribution in response to infection or other stimuli are primarily due to increased NK cell production in the marrow and possibly in part to proliferation of mature peripheral NK cells.12
Mature NK cells are mostly present in peripheral blood, where they represent approximately 15 percent of lymphocytes (but with large individual variations), and in the spleen; they are rare or absent in other lymphoid organs.2,13 Natural killer cells do not normally recirculate through the thoracic duct. In the marrow, they represent less than 1 percent of the cells, indicating that a pool of preformed NK cells is not sequestered in the marrow. Small numbers of NK cells can be identified in the liver (pit cells), lung, and intestinal mucosa.14,15 Upon activation, as, for example, in response to interferon or viral or bacterial infections, NK cells may accumulate in organs in which they are normally rare, particularly the liver and marrow.12 Cells with characteristics of activated NK cell (decidual granulocytes) represent the predominant cell type present in the human early pregnancy decidua.16 The physiologic significance of these cells in the decidua is not clear, but they might have a role in facilitating embryonic implantation, in allowing placenta and embryo growth, or in the modulation of the maternal immune response against embryo antigens.
Cytotoxicity mediated by NK cells depends on binding to the target cells, followed by activation of the lytic mechanism, which usually involves secretion of the granules, including molecules with lytic ability, such as the pore-forming proteins and granzymes.4 Cytotoxicity is also mediated through the interaction of surface molecules, for example, the interaction of Fas ligand on NK cells with Fas receptor on target cells. Lysis of the target cells is due both to the alteration of membrane permeability and to induction of apoptosis (see Chap. 11).4 A number of surface molecules have been identified on NK cells that, when stimulated, activate the cytotoxic mechanism.17 The best characterized of these molecules is the low-affinity receptor for the Fc fragment of IgG (FcgIIIA or CD16) expressed on virtually all human NK cells in association with the signal-transducing CD3e or FceRIg chains. When CD16 is cross-linked by IgG antibodies bound to a target cell surface, it triggers antibody-dependent cell-mediated cytotoxicity.13,18 Other molecules, including receptors able to activate the cytotoxic mechanism and adhesion molecules facilitating the effector–target cell contact, have been shown to be involved in target cell recognition and triggering of the cytotoxic mechanisms. CD16 is not required, in the absence of antibodies, for NK cell cytotoxicity.17
Based on the observation that NK cells preferentially kill certain tumor cells lacking expression of MHC class I molecules, Kärre et al19 proposed that NK cells may detect and eliminate autologous cells lacking MHC class I. This led to the hypothesis that NK cells are regulated by positive signals initiated by activating receptors and negative signals transmitted by putative interactions between inhibitory receptors for MHC class I on the NK cells and autologous MHC class I molecules on potential target cells. A mechanism for immune surveillance against cells that lose expression of MHC class I would be advantageous because, in the absence of class I, these abnormal cells would escape elimination by CTL. Numerous viruses inhibit the synthesis or transport of MHC class I proteins (see Chap. 138), presumably to avoid detection by CTL.20 In addition, frequent loss of MHC class I expression on tumor cells has been documented.21
In humans, two types of NK cell receptors for MHC class I have been identified. The killer-cell Ig-like receptors (KIR) are encoded by about 10 genes present on human chromosome 19q13.4.22 Certain KIR molecules bind HLA-C ligands, whereas other KIR recognize HLA-B. Another class of NK cell receptors are heterodimeric glycoproteins composed of a CD94 subunit disulfide-bonded to an NKG2 molecule.22 The CD94 and NKG2 genes are on human chromosome 12p12-p13 and are members of the C-type lectin superfamily. The CD94/NKG2 receptor binds to a nonclassical MHC class I molecule, HLA-E, that is unusual in that the peptides present in the HLA-E binding groove are usually leader segments derived from HLA-A, -B, -C, or -G proteins.23 When synthesis of HLA-A, -B, -C, or -G is disrupted, possibly by viral infection of the host cell, HLA-E cannot be transported to the cell surface for presentation to the CD94/NKG2 receptor. The various KIR and CD94/NKG2 receptors are expressed on overlapping subsets within the NK cell population and also on certain memory T cells. The observation that F1 mice reject marrow grafts from their parents can now be explained by the existence of NK cell subpopulations in the F1 recipient that lack appropriate NK cell receptors for the grafted parental cells.24 The KIR molecules and the CD94/NKG2A receptor have an immunoreceptor tyrosine-based inhibitory motif (ITIM) sequence in their cytoplasmic domains, which bind to the cytoplasmic tyrosine phosphatase SHP-1, resulting in inhibition of NK cell cytotoxicity and cytokine secretion.22 Therefore, the functional behavior of NK and T cells expressing KIR or CD94/NKG2 is likely regulated by the balance of positive signals transmitted by a variety of activating receptors and negative signals (resulting in phosphatase recruitment) provided by the inhibitory MHC class I receptors.
Certain receptors of the KIR and CD94/NKG2 families do not possess ITIM sequences and activate, rather than suppress, NK and T cell responses.22 These receptors noncovalently associate with the homodimeric adapter protein DAP12.25 Like the CD3e and the FceRI-g subunits, DAP12 contains an immunoreceptor tyrosine-based activation motif in the cytoplasmic domain. Upon receptor li-gation, DAP12 becomes tyrosine phosphorylated, recruits cytoplasmic tyrosine kinases, and induces cellular activation.25 As yet, the physiologic role of activating NK cell receptors for MHC class I has not been determined, but may have consequences in allogeneic marrow transplantation.
Although resting peripheral blood NK cells are cytotoxic, their activity can be greatly enhanced by both in vivo or in vitro exposure to cytokines such as IFN-a/b, IL-2, IL-12, IL-15, and IL-18.26,27 and 28 Resting NK cells express intermediate-affinity IL-2 receptors, and IL-2 induces the progression of most NK cells into the cell cycle.29
Many of the physiologic functions of NK cells are mediated at least in part by their ability to secrete cytokines. Natural killer cells are powerful producers of IFN-g and granulocyte-macrophage colony stimulating factors (GM-CSF) and have also been shown to be able to produce tumor necrosis factor-a (TNF-a), macrophage-CSF (M-CSF), IL-3, IL-5, IL-8, IL-13, and other cytokines.2,27,30,31 and 32 Stimulation by cytokines such as IL-2, IL-12, IL-18, TNF-a, and IL-1 and triggering of surface receptors, such as CD16 interaction with immune complexes, are among the stimuli that, acting individually or often in synergistic combination, induce NK cells to produce cytokines.2,33,34
Because of their ability to respond to external stimuli without previous sensitization, NK cells are able to respond rapidly, although nonspecifically, to the presence of infectious microorganisms or, in some cases, neoplastic cells. Together with phagocytic cells, NK cells are effectors of the innate or natural resistance, which represents the first line of defense against infection (Fig. 85-1).

FIGURE 85-1 Schematic depiction of some of the functions and regulatory pathways of NK cells as effector cells of natural resistance. In addition to mediating cytotoxicity, NK cells exert their physiologic roles by releasing several cytokines that affect the functions of other cell types, including hematopoietic cells. Natural-killer-cell activity is also regulated by cytokines. Cytokines IFN-a/b, IL-2, and IL-12 enhance NK-cell-mediated cytotoxicity. IL-2, IL-12, TNF, and IL-1 induce NK-cell lymphokine production. IL-2 and IL-12 induce NK-cell proliferation. The arrows with a + in the figure indicate stimulatory effects resulting in lymphokine secretion, enhancement of NK-cell cytotoxic activity, or activation of phagocytic cells.

The ability of NK cells to participate in the resistance against infection by certain viruses is well documented in experimental animals35 and is strongly suggested by the recurrent viral infections in the few patients described to have a selective deficiency of NK cells.36 In vitro NK cells selectively kill virus-infected cells with a mechanism that is at least in part dependent on the production of IFN-a, a potent stimulator of NK cell activity.37,38 In vivo virus infection and IFN production are usually accompanied by a rapid activation of and increase in the number of NK cells, both systemic and localized in the infected area.12 The NK response to virus infection usually peaks at 3 days postinfection and is followed by an antigen-specific T-helper and CTL response, which peaks 7 to 9 days postinfection.12 The early NK response induces a significant reduction in the titer of certain viruses, including murine cytomegalovirus.35 Other viruses, such as lymphocytic choriomeningitis virus (LCMV), are resistant to the antiviral effects of NK cells, and NK cell activation induced by these viruses has pathogenic effects.35
Natural killer cells have been described to be directly cytotoxic for bacteria and certain parasites.39 Most important, NK cells enhance the response of phagocytic cells to microorganisms, especially intracellular bacteria and parasites, by producing high levels of the phagocyte-activating cytokines IFN-g and GM-CSF in response to the microorganisms themselves or to factors such as IL-12 and TNF-a produced by infected phagocytic cells.40,41
The observation that NK cells kill in vitro–transformed or tumor-derived cell lines has been used to support the theory that, in immune surveillance, NK cells, rather than T cells, can recognize and kill newly arising malignant tumor cells.42 In experimental animals, the in vivo activity of NK cells against tumors was investigated by evaluating their effects on long-term growth of tumors, metastasis formation, and short-term elimination of radiolabeled tumor cells.2 Experiments have clearly shown that NK cells can destroy tumor cells in vivo, and there is some evidence for an effective role of NK cells in resistance to spontaneously arising neoplastic cells. Thus, in human cancer patients, NK cell cytotoxic activity is often decreased, and several studies have suggested that increased NK cell activity tends to correlate with increased survival times and longer intervals before metastasis is ob-served.43,44 However, the hypothesis of a role for NK cells in immune surveillance is not yet supported by statistical evidence indicating a correlation between low tumor incidence and high NK cell cytotoxic activity.45
Natural killer cells, by interacting with infectious agents and antigens early during the immune response, have either stimulatory or inhibitory effects on the function of B and T cells, as well as on antigen-presenting cells.2 Evidence for an enhancing effect of NK cells on B-cell response has been shown both in vitro and in vivo by studies demonstrating that NK cells in the absence of T cells support antigen-specific B-cell responses, in part by producing IFN-g.46,47 In certain bacterial and parasitic infections, NK cells may be necessary for optimal induction of a T-helper type 1 response. Natural killer cells stimulated by microorganisms or by cytokines such as IL-12 and TNF produce large amounts of IFN-g and other cytokines that facilitate T-helper-cell type 1 development.48,49
Experimental observations in animals, clinical findings in human patients, and in vitro analyses provided strong evidence that NK cells are involved in the regulation of hematopoiesis.50 The effector role of NK cells in rejection of parental marrow graft in irradiated F1 mice51 and in suppressing erythropoiesis and phagocytopoiesis in mice infected with LCMV52 demonstrated that in vivo activated NK cells can affect both allogeneic and syngeneic hematopoietic progenitor cells. Because of the ability of NK cells to kill malignant hematopoietic cells, they have been postulated to play an important role in the graft-versus-leukemia reaction in allogeneic marrow transplantation while playing only a modest, if any, role in graft-versus-host disease (see Chap. 18).53
In vivo depletion of NK cells by treatment of mice with anti-NK cell antibodies produces differential effects on various lineages. Natural killer cell depletion in normal mice increases phagocytopoiesis and decreases erythropoiesis and megakaryocytopoiesis.54,55 Consistent with these results, depletion of NK cells in mice receiving myelosuppressive irradiation results in faster recovery of phagocytopoiesis and slower recovery of megakaryocytopoiesis and erythropoiesis.56 Clinical evidence for a role of NK cells in the regulation of human hematopoiesis is provided by the demonstration that NK cells are the effector cells mediating suppression of hematopoiesis in some cases of acquired aplastic anemia in both acute and chronic monoclonal NK lymphocytosis and possibly in other clinical conditions.50 In vitro studies have shown that NK cells have a prevalent inhibitory effect on colony formation from hematopoietic progenitor cells.57,58 However, NK cells enhance formation of megakaryocytic colonies and, in some experimental conditions, of erythroid and granulocyte-macrophage colonies.31,59 The effect of NK cells is mostly mediated by secretion of humoral factors and may require the participation of accessory cells.58 Natural killer cells, constitutively or upon activation, produce several lymphokines, some with mostly inhibitory effects on hematopoiesis, such as TNF and IFN-g, and some with mostly positive effects, such as GM-CSF, M-CSF, and IL-3.30,31
Natural killer cell function and, in some, NK cell numbers are often decreased in pathologic conditions, including cancer and AIDS (see Chap. 89).43,60 The reduced activity or number of NK cells may contribute to the pathology of the disease by decreasing the innate resistance against tumor growth and metastasis in cancer patients or against opportunistic infections in AIDS patients. The complete congenital absence of NK cells is extremely rare and characterized clinically by recurrent, severe viral infections.36 An NK hyporesponsiveness is observed in patients with Chediak-Higashi syndrome (see Chap 72),61 a rare autosomal recessive disease associated with cellular dysfunction, including fusion of cytoplasmic granules and defective degranulation of neutrophil lysosomes. Natural killer cells in these patients are in normal numbers but present a single, large granule in the cytoplasm and have a severely reduced ability to mediate cytotoxicity.61
Malignant acute expansion of NK cells is rare; it occurs both in the nasopharyngeal region and in nonnasal areas as an NK cell (CD2+, CD3 –, CD56+, CD16–, CD57–) leukemia or lymphoma that mostly affects extranodal tissues (see Chap. 96 and Chap. 100). It usually has an extremely aggressive clinical course. It may be associated with Epstein-Barr virus infection.62,63 and 64 More commonly observed is a chronic monoclonal proliferative disorder of large granular lymphocytes with a clinical course that is often relatively benign.65 Most patients have lymphocytic infiltration of the marrow, and severe neutropenia and anemia are often observed. Associated diseases, most commonly rheumatoid arthritis, hepatitis, or cancer, are present in up to half of the patients.65 Although cells from all these patients are characterized by an LGL morphology, in approximately two-thirds of the cases they represent a monoclonal expansion of CD8+ T cells, and in only less than one-third do they have the typical phenotype and genotype of CD3–, CD56+, CD57+, and, in some patients, CD16+ NK cells.65

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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