Chapter 32 : Measurement of NK Cell Phenotype and Activity in Humans

Abstract:

Natural killer (NK) cells are a subset of innate lymphocytes initially identified for their ability to specifically kill virally infected and transformed cells without prior antigen sensitization. NK cells efficiently kill target cells through directed release of perforin-containing secretory lysosomes, a feature shared with cytotoxic T lymphocytes (CTLs) (1). Despite similarities in effector mechanisms, the strategies employed by NK cells and CTLs for target cell recognition are distinct yet complementary with respect to immune defense. Whereas CTLs express recombined, clonally distributed antigen receptors that dictate their activation and are selected for recognition of cells presenting nonself peptides in the context of major histocompatibility (MHC) class I molecules, NK cells rely on dynamic integration of signals from various germ line-encoded receptors for target cell discrimination. NK cells express numerous inhibitory receptors to detect normal expression of MHC class I and can selectively kill target cells that downregulate these molecules (2). NK cell activation by target cells with low MHC class I levels does not occur by default, but rather is mediated through engagement of different activating receptors (3). Representing an effector arm of humoral immunity, NK cells express the low-affinity Fc receptor CD16, which facilitates antibody-dependent cellular cytotoxicity (4). Moreover, supporting first-line defense against virally infected or stressed cells, a multiplicity of activating receptors that participate in natural cytotoxicity have been identified. In general, engagement of each such receptor alone is not sufficient to induce NK cell cytotoxicity. However, certain combinations of receptor signals can synergistically activate NK cell effector functions (5). Reflecting the expression of several activating receptors on NK cells that bind ligands exclusively expressed on hematopoietic cells, the ability of NK cells to kill autologous, activated immune cells is increasingly appreciated as an important immunoregulatory mechanism to control and shape adaptive immune responses (6). Upon activation, NK cells not only release granules but also abundantly produce chemokines and cytokines (7).