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1190 Part IX: Lymphocytes and Plasma Cells Chapter 77: Functions of Natural Killer Cells 1191

as IFN-α/β, IL-2, IL-12, IL-15, and IL-18. 32–34 Resting NK cells constitu- activation induced by viral infection may have beneficial or pathogenic
tively express intermediate-affinity IL-2 receptors, and IL-2 induces the effects. After expansion in response to MCMV infection, NK cells
44
progression of most NK cells into the cell cycle. 35 expressing the activating Ly49H receptor persist for several months and
respond rapidly to rechallenge with MCMV, thus possessing immuno-
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PRODUCTION OF CYTOKINES logic memory. Similarly, a subset of liver-resident NK cells can mediate
antigen-specific contact hypersensitivity responses and immunologic
Many of the physiologic functions of NK cells are mediated at least partly memory. 45,46
by their ability to secrete cytokines. NK cells are powerful producers of NK cells enhance the response of phagocytic cells to microorgan-
IFN-γ and GM-CSF, and other cytokines and chemokines. Stimulation isms, especially intracellular bacteria and parasites, by producing high
by cytokines, such as IL-2, IL-12, IL-18, TNF-α, and IL-1, 2,33,36,37 and trig- levels of the phagocyte-activating cytokines IFN-γ and GM-CSF in
gering by activating receptors, such as CD16 interacting with immune response to the microorganisms themselves or to factors, such as IL-12
complexes, are among the stimuli that, acting individually or often in and TNF-α, produced by infected phagocytic cells. 47,48
synergistic combination, induce NK cells to produce cytokines. 2,38,39
REGULATION OF ADAPTIVE IMMUNITY
PHYSIOLOGIC ROLES OF NATURAL NK cells, by interacting with infectious agents and antigens early during
KILLER CELLS the immune response, have either stimulatory or inhibitory effects on
the function of B and T cells and antigen-presenting cells. Evidence
2
INNATE RESISTANCE for an enhancing effect of NK cells on B-cell responses has been shown
both in vitro and in vivo by studies demonstrating that NK cells in the
Together with myeloid cells, NK cells are effectors of the innate or natu- absence of T cells support antigen-specific B-cell responses, partly by
ral resistance, which represents the first line of defense against infection producing IFN-γ. 49,50 In certain infections, NK cells may be necessary
(Fig. 77–2). The ability of NK cells to participate in the resistance against for optimal induction of both a CD4 and CD8 T-cell response. 51,52
+
+
infection by certain viruses is well documented in experimental animals NK cells stimulated by microorganisms or by cytokines, such as IL-12
and is strongly suggested by the recurrent viral infections in the rare and IL-18, produce large amounts of IFN-γ and other cytokines that
patients with a selective deficiency of NK cells. NK cells selectively kill facilitate T-helper cell type 1 development. 53,54 The reciprocal activating
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virus-infected cells by a mechanism that is at least partly dependent on interaction between NK cells and the antigen-presenting dendritic cells
the production of IFN-α, a potent stimulator of NK cell activity. 41,42 In is important for the regulation of both innate resistance and the down-
vivo viral infection and type I IFN production usually are accompanied stream adaptive response to pathogens. 55,56
by rapid activation of, and increase in the number of, NK cells. The
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NK cell response to virus infection is followed by an antigen-specific
T helper and CTL response, which peaks 7 to 9 days after infection. MODULATION OF HEMATOPOIESIS
18
The early NK cell response induces a significant reduction in the titer of Experimental and clinical studies have demonstrated that NK cells are
certain viruses, including mouse cytomegalovirus (MCMV). NK cell involved in the regulation of hematopoiesis. The effect of NK cells
57
43

Figure 77–2. Schematic of some of the func-
tions and regulatory pathways of natural killer
(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 progenitor cells.
NK cell activity also is regulated by cytokines.
Cytokines interferon (IFN)-α/β, interleukin (IL)-2,
IL-15, and IL-12 enhance NK-cell–mediated cyto-
toxicity. IL-2, IL-12, IL-15, IL-18, tumor necrosis
factor (TNF), and IL-1 induce NK cell lymphokine
production. IL-2 and IL-12 induce NK cell pro-
liferation. Blue arrows indicate conditions that
activate NK cells whereas the red arrows indicate
innate, proinflammatory, and immunoregulatory
functions of NK cells. GM-CSF, granulocyte-mac-
rophage colony-stimulating factor; M-CSF, mac-
rophage colony-stimulating factor.

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