Natural killer (NK) cells, with a predominant morphology of large granular lymphocytes, represent a lineage of lymphoid cells with constitutive ability to mediate cytotoxicity toward pathologic target cells and secrete cytokines. NK cells participate in the innate resistance to microbial pathogens and malignancies; opposing effects of activating and inhibitory receptors regulate NK cell activity. Malignant expansions of NK cells, either acute or chronic, are rare, but represent well-identified clinical entities.
Acronyms and Abbreviations
ADCC, antibody-dependent cell-mediated cytotoxicity; AML, acute myelogenous leukemia; CAR, chimeric antigen receptor; CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA, human leukocyte antigen; IFN, interferon; Ig, immunoglobulin; IL, interleukin; ILC, innate lymphoid cell; iNKT, invariant natural killer T cell; ITIM, immunoreceptor tyrosine-based inhibitory motif; KIR, killer cell Ig-like receptor; LCMV, lymphocytic choriomeningitis virus; LGL, large granular lymphocyte; MCMV, mouse cytomegalovirus; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell antigen receptor; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.
IDENTIFICATION AND DEFINITION OF NATURAL KILLER CELLS
Natural killer (NK) cells were identified in the blood and lymphoid organs of humans and experimental animals as cells capable of killing tumors, virus-infected cells, and, in some instances, normal cells, in the absence of previous deliberate or known sensitization.1,2 NK cells are now considered to belong to the cellular subgroup that is characterized by the production of interferon (IFN)-γ within the family of innate lymphoid cells (ILCs), a family of developmentally related cells involved in innate immunity and tissue development.3 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 receptor (TCR) chains nor express on their surface the CD3-TCR complex; (2) express the CD56 (N-CAM), CD335 (NKp46), and CD16 (FcγRIIIA), antigens in humans, the NK1.1 (NKR-P1C), NKp46, and DX5 (VLA-2/CD49d) antigens in mice, and the NKR-P1 antigen in rats; and (3) can kill cells not expressing major histocompatibility complex (MHC) class I or class II antigens. Thus, target-cell recognition by NK cells is distinct from cytotoxic T lymphocytes (CTLs), which recognize specific antigenic peptides bound to MHC class I molecules. Nonetheless, the presence of MHC class I on 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 activity 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 natural killer T (iNKT) cells express an invariant TCR that recognizes glycolipids presented by CD1d, a nonclassical MHC molecule, and upon stimulation rapidly produce large amounts of IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and IL-13.4