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C H A P T E R 22

NATURAL KILLER CELL IMMUNITY

Don M. Benson, Jr. and Michael A. Caligiuri

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Natural killer (NK) cells are large, granular lymphocytes comprising Other antigens are differentially expressed by CD56 NK cells
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about 10% to 15% of the peripheral circulation. First characterized and provide insight into their functional role in the immune response.
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by their ability to lyse targets independent of activating or initiating For example, CD56 NK cells also exhibit relatively high surface
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stimuli, NK cells are a critical cellular component of the innate density expression of killer immunoglobulin-like receptors (KIRs).
immune system. In addition, NK cells secrete cytokines that help NK cell KIR expression appears important in preventing autoim-
to marshal and shape the innate and adaptive immune response to munity and in surveying against malignant transformation. 16,18
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infection and malignant transformation. There has been a recent Both CD56 and CD56 bright NK cells express modest levels of
surge of interest in NK cells as new discoveries in both the laboratory chemokine (C-X-C motif) receptor 3 (CXCR3). However, in contrast
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and the clinic have characterized the crucial contributions of NK cells to CD56 bright NK cells, CD56 NK cells display relatively abundant
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in shaping the early immune response. NK cells play a key role in surface expression levels of CXCR1, CXCR4, and CX3CR1.
maintaining host defense, as exemplified in human NK cell deficiency CXCR1 binds IL-8, and CXCR4 binds stromal cell–derived factor
syndromes (which carry increased susceptibility to overwhelming 1 (SDF-1). These cytokines are associated with local inflammatory
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viral, intracellular, and atypical mycobacterial infections) and in response; for example, IL-8 levels are increased in the setting of
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animal models of NK cell deficiency (e.g., such mice are particularly acute viral infections, and IL-8 and SDF-1 levels are increased
6,7
susceptible to developing cancer). This chapter reviews current with solid 21,22 and hematopoietic malignancies. 23,24 Thus expression
understanding of NK cell biology, the role of NK cells in human of these chemokine receptors allows NK cells to traffic to local areas
diseases, and the recent clinical applications of NK cells in cancer of inflammatory response to mediate antiviral and antitumor activity.
therapy.
CD56 bright Natural Killer Cells
FUNDAMENTAL BIOLOGY
CD56 bright NK cells play more of an immunoregulatory role.
Natural Killer Cell Subsets CD56 bright NK produce a multitude of cytokines and chemokines,
have a relatively high proliferative capacity, reside primarily in the
NK cells are phenotypically recognized by surface expression of parafollicular T cell–rich region of secondary lymphoid tissue (SLT),
CD56 (also called neural cell adhesion molecule) and the absence and have modest cytolytic granules, KIR, and FcγRIII expression (see
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of the T cell–specific surface antigen CD3 as well as the T-cell Table 22.1). CD56 bright NK cells are unique among cytotoxic effec-
8,9
receptor. Based on the intensity of CD56 surface expression, tor cells in their constitutive expression of the high-affinity IL-2Rαβγ
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two functional subsets (so-called CD56 bright and CD56 ) of NK complex, making them responsive to picomolar concentrations of
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cells may be discriminated from one another. CD56 NK cells IL-2 released by activated T cells in the parafollicular T cell–rich
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comprise 85% to 90% of the NK cells in peripheral circulation region of SLT. As noted, CD56 bright NK cells comprise only about
and are potent mediators of cytotoxicity. About 10% to 15% of 10% of the circulating NK population but predominate almost to
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NK cells in the circulation are CD56 bright , and upon activation, this the exclusion of the CD56 NK subset in SLT. 2,26 This likely results
2
subset is capable of robust cytokine and chemokine production. from their selective expression of a number of receptors that assist in
Fig. 22.1 graphically represents the NK subsets described later, and homing cells to and retaining cells in SLT (e.g., CCR7 and CD62L). 10
Table 22.1 summarizes major surface antigens associated with each The ability of CD56 bright NK cells to produce an abundant variety
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NK cell subset. of cytokines and chemokines compared with the CD56 subset
likely relates more to the differential expression of both negative and
positive regulators of cytokine/chemokine production and less to
CD56 Natural Killer Cells constitutive expression of cytokine-activating receptors. For example,
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CD56 bright NK cells have little or no expression of two negative
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CD56 NK cells have exquisite cytolytic properties and are able to regulators of cytokine/chemokine production, namely SHIP-1 (Src
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kill infected as well as tumor cell targets without prior sensitization. homology 2 domain-containing inositol 5-phosphatase 1) and HLX
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They constitutively express the interleukin-2/15 (IL-2/IL-15) recep- (H2.0-like homeobox 1), 27,28 but CD56 NK cells lack constitutive
tor (R) β- and common γ-receptor chains, which together form a expression of a positive regulator of cytokines called SET. 29
receptor complex through which cells may respond to stimulation by
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either IL-2 or IL-15. 11,12 CD56 NK cells can lyse tumor cell targets
through at least three distinct mechanisms. First, they can execute NATURAL KILLER CELL DEVELOPMENT
cytotoxicity through granule exocytosis of perforin and granzyme. 13,14
Second, cytotoxicity can be mediated through Fas ligand and tumor NK cells are prototypic, founding members of a population of cells
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necrosis factor (TNF)-related apoptosis-inducing ligand associated referred to as innate lymphoid cells (ILC). Three populations of
with production of cytokines, including interferon-γ (IFN-γ), TNF- ILC have been described based on differential expression of specific
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α, and granulocyte macrophage colony-stimulating factor. Third, transcription factors and cytokine production, and NK cells are
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CD56 NK cells can mediate antibody-dependent cytotoxicity believed to arise from group 1 ILCs, which are characterized by
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(ADCC) via the high-density surface expression of CD16 (the FcγRIII T-bet and EOMES expression. Acquisition of the IL-15 recep-
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receptor). 2,16 Freshly isolated, unstimulated CD56 NK cells have tor (CD122) is likely a first step toward NK cell differentiation
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intrinsically greater cytotoxicity against NK-sensitive targets such as from CD34 hematopoietic stem cells and a subsequent common
the K562 cell line in vitro compared with the CD56 bright NK cells. 17 lymphoid precursor cell. Moreover, IL-15 is required for NK cell
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