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Natural killer (NK) cells, with a predominant morphology of large granular lymphocytes, represent a third lineage of lymphoid cells with constitutive ability to mediate cytotoxicity of pathologic target cells and secrete cytokines. NK cells participate in the innate resistance to intracellular pathogens and malignancies and have a modulatory effect on adaptive immunity and hematopoiesis. NK cell activity is 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

Acronyms and abbreviations that appear in this chapter include: CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA, human leukocyte antigen; IFN, interferon; Ig, immunoglobulin; IL, interleukin; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; KIR, killer cell immunoglobulin-like receptor; LCMV, lymphocytic choriomeningitis virus; LGL, large granular lymphocyte; M-CSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; NK, natural killer; NKG2, killer cell lectin-like receptor family; R, receptor; Syk, spleen tyrosine kinase; TCR, T-cell antigen receptor; TNF, tumor necrosis factor; YIMN, tyrosine-containing motif.


Natural killer (NK) cells originally were identified in the 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 NK cells are defined as cytotoxic cells with the predominant morphology of large granular lymphocytes (LGLs) that (1) neither productively rearrange any of the genes encoding the T-cell antigen 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 (FcγRIIIA), CD335 (NKp46), and CD56 (NCAM) antigens in humans (see Chap. 15, Table 15–1), the NK1.1 (NKR-P1C), NKp46 (Ly94), and DX5 (VLA-2/CD49d) antigens in the mouse, and the NKR-P1 antigen in the rat; (3) mediate cytolytic reactions even in the absence of major histocompatibility complex (MHC) class I or class II antigen expression on the target cells. Target cell recognition by NK cells is clearly distinct from cytotoxic T lymphocytes (CTLs), which recognize specific antigenic peptides in association with MHC class I molecules. Cytotoxicity mediated by NK cells often is defined as non-MHC requiring, distinguishing it from the MHC-restricted cytotoxicity mediated by CTL. Nonetheless, the presence of MHC class I on target cells can affect NK cell recognition, in some cases inhibiting an NK cell response against cells expressing MHC class I. Certain T lymphocytes that express either an αβ or a γδ TCR may exhibit, particularly upon activation, TCR-independent cytolytic activity that resembles that of NK cells. Among the T lymphocytes displaying NK-like cytotoxicity or non–MHC-requiring cytotoxicity, NK T cells are a subset of cytotoxic T cells expressing in the mouse NK1.1 and with a restricted αβ TCR diversity. The majority of NK T cells recognize glycolipids presented by CD1d, a ...

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