Natural Killer Cell Function

The role of an NK cell is two fold: to kill virally infected cells and tumour cells that are encountered within the body and to stimulate other arms of the immune system through cytokine release. NK cells can kill their targets by means of several different mechanisms (Fig. 1). Antibody-dependent cellular cytotoxicity (ADCC) is initiated by the binding of CD 16 to the Fc portion of antibodies that are in turn bound to cell-associated antigens on potential targets. "Natural" or spontaneous cytotoxicity is the ability to kill without prior activation or proliferation and without antibody. This type of killing is controlled by a collection of receptors that bind ligands on target cells, determining whether these cells are stressed, tumorigenic, or virally infected rather than normal. NK cells can also kill via interactions between Fas ligand (FasL) and Fas. In this case, binding of FasL on NK cells to Fas on the target cells induces apoptosis of the target cells.

Another important feature of NK cells is their ability to produce cytokines that activate other elements of the immune response. When activated by their receptors, NK cells produce interferon^ (IFN-y) and tumour necrosis factor (TNF), cytokines with antiviral functions and the ability to stimulate inflammatory immune responses. NK cells are also regulated by cytokines; cytokines such as interleukin-2 (IL-2), IL-12 and IFN-a/p induce cytotoxic activity and stimulate cytokine production.

Cytokine production

Activating receptor & signal transducing molecule

Fc receptor and associated molecules

Inhibitory receptor ligand

Activating receptor & signal transducing molecule

Fc receptor and associated molecules

Inhibitory receptor

ligand

ITIMs

Natural cytotoxicity

Antibody dependent cellular cytotoxicity

Target cell apoptosis

ITIMs

Natural cytotoxicity

Antibody dependent cellular cytotoxicity

Figure I. Types of receptors ami their effects in NK cells. In addition to an Fc receptor ami Fas ligand, NK cells express different lypes of'activating anil inhibitory recepiors. When hound to ligand, the activating reeepiors send signals driving natural cytotoxicity, and inhibitory receptors may block these signals. The Fc receptor, when bound to the Fc portion of an antibody, signals for antibody dependent cellular cytotoxicity. The Fas ligand, upon binding to Fas on the target cells, results in signals within the target cell thai drive its apoptosis. Activation of the NK ceil also results in cytokine production that can activate other cells of the immune system.

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