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CHAPTER 77 histocompatibility complex (MHC) class I or class II antigens. Thus,
target-cell recognition by NK cells is distinct from cytotoxic T lym-
FUNCTIONS OF NATURAL phocytes (CTLs), which recognize specific antigenic peptides bound to
MHC class I molecules. Nonetheless, the presence of MHC class I on
KILLER CELLS target cells affects NK cell recognition, in some cases inhibiting a NK
cell response.
Certain T lymphocytes that express either αβ or a γδ TCR may
exhibit, particularly upon activation, TCR-independent cytolytic activ-
Giorgio Trinchieri, Richard W. Childs, and Lewis L. Lanier ity that resembles that of NK cells and often express many of the same
surface receptors as NK cells. Among the T lymphocytes in humans
and mice that coexpress many of the NK cell antigens, invariant natu-
ral killer T (iNKT) cells express an invariant TCR that recognizes gly-
SUMMARY colipids presented by CD1d, a nonclassical MHC molecule, and upon
stimulation rapidly produce large amounts of IFN-γ, granulocyte-mac-
Natural killer (NK) cells, with a predominant morphology of large granular rophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and
lymphocytes, represent a lineage of lymphoid cells with constitutive ability to IL-13. 4
mediate cytotoxicity toward pathologic target cells and secrete cytokines. NK
cells participate in the innate resistance to microbial pathogens and malignan-
cies; opposing effects of activating and inhibitory receptors regulate NK cell MORPHOLOGY
activity. Malignant expansions of NK cells, either acute or chronic, are rare, but Human LGLs are medium- to large-size lymphocytes with round or
represent well-identified clinical entities. indented nuclei, condensed chromatin, and usually prominent nucle-
oli. The cytoplasm is abundant and contains a variety of organelles and
granules (primary lysosomes) that, in addition to lysosomal enzymes,
contain proteins important for cytotoxic function, such as serine
IDENTIFICATION AND DEFINITION esterases (granzymes) and pore-forming proteins (perforin). Although
5
many NK cells have the morphology typical of LGL, a significant pro-
OF NATURAL KILLER CELLS portion of NK cells are agranular and indistinguishable from other
lymphocytes. 6
DEFINITION
Natural killer (NK) cells were identified in the blood and lymphoid
organs of humans and experimental animals as cells capable of killing ORIGIN AND TISSUE DISTRIBUTION
tumors, virus-infected cells, and, in some instances, normal cells, in the NK cells originate in the marrow from the common lymphoid progen-
absence of previous deliberate or known sensitization. NK cells are itor cell. Most have a life span ranging from a few days to a few weeks,
1,2
7
8
now considered to belong to the cellular subgroup that is characterized but some may persist for months after exposure to viral challenge. In
9
by the production of interferon (IFN)-γ within the family of innate lym- mice, the cytokine IL-15 plays a particularly important role in the dif-
phoid cells (ILCs), a family of developmentally related cells involved ferentiation and expansion of NK cells. NK cell differentiation does
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in innate immunity and tissue development. NK cells are defined as not require the thymus, although NK cell progenitors can differentiate
3
cytotoxic cells with the predominant morphology of large granular in the thymus from precursors expressing IL-7Rα CD127. Second-
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lymphocytes (LGLs) that: (1) neither productively rearrange any of ary lymphoid tissues may also be a site of NK cell development in
the genes encoding the T-cell receptor (TCR) chains nor express on humans. The increased number of NK cells and altered anatomical
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their surface the CD3-TCR complex; (2) express the CD56 (N-CAM), distribution in response to infection or other stimuli are the result
CD335 (NKp46), and CD16 (FcγRIIIA), antigens in humans, the NK1.1 of increased NK cell production in the marrow and proliferation of
(NKR-P1C), NKp46, and DX5 (VLA-2/CD49d) antigens in mice, and peripheral NK cells.
the NKR-P1 antigen in rats; and (3) can kill cells not expressing major NK cells represent approximately 5 to 20 percent of blood lympho-
cytes. Immature NK cells express high amounts of CD56, lack CD16,
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and have low cytolytic capacity, whereas mature NK cells in blood
express low amounts of CD56, high levels of CD16, and mediate potent
14
Acronyms and Abbreviations: ADCC, antibody-dependent cell-mediated lytic activity. NK cells are present in the red pulp of the spleen and are
2
cytotoxicity; AML, acute myelogenous leukemia; CAR, chimeric antigen found at a low frequency in other lymphoid organs and marrow. NK
receptor; CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte-macrophage cells with a phenotype resembling the CD56 high peripheral subset have
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colony-stimulating factor; HLA, human leukocyte antigen; IFN, interferon; been detected in lymph nodes. Small numbers of NK cells can be iden-
Ig, immunoglobulin; IL, interleukin; ILC, innate lymphoid cell; iNKT, invari- tified in the liver (pit cells), lung, and intestinal mucosa. 16,17 In response
ant natural killer T cell; ITIM, immunoreceptor tyrosine-based inhibitory to type I IFN or viral or bacterial infections, NK cells accumulate in
organs in which they normally are rare, particularly the liver, marrow,
motif; KIR, killer cell Ig-like receptor; LCMV, lymphocytic choriomeningitis and lymph nodes where they may produce large amounts of cytokines.
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virus; LGL, large granular lymphocyte; MCMV, mouse cytomegalovirus; MHC, CD56 bright CD16 NK cells are the predominant cell type present in the
–
major histocompatibility complex; NK, natural killer; TCR, T-cell antigen human early pregnancy decidua. Decidual NK cells produce cytokines
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receptor; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing that have tissue remodeling capacity, facilitate embryonic implantation,
ligand. monitor mucosal integrity throughout the menstrual cycle, control
trophoblast invasion during pregnancy, and modulate the maternal
immune response against embryo antigens. 19

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