Antibody Dependent Cell Mediated Cytotoxicity

A number of cells that have cytotoxic potential express membrane receptors for the Fc region of the antibody molecule. When antibody is specifically bound to a target cell, these receptor-bearing cells can bind to the antibody Fc region, and thus to the target cells, and subsequently cause lysis of the target cell. Although these cytotoxic cells are nonspecific for antigen, the specificity of the antibody directs them to specific target cells. This type of cytotoxicity is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC).

Among the cells that can mediate ADCC are NK cells, macrophages, monocytes, neutrophils, and eosinophils. Antibody-dependent cell-mediated killing of cells infected with the measles virus can be observed in vitro by adding anti-measles

Class I MHC CD94/NKG2

AR-ligand AR Normal cell NK cell

AR-ligand AR Normal cell NK cell

KIR and/or CD94/NKG2

KIR and/or CD94/NKG2

Opposing Signals Model Cells

FIGURE 14-14

NK cell

Killing

AR-ligand Virus-infected cell ( class I MHC)

FIGURE 14-14

NK cell

Opposing-signals model of how cytotoxic activity of NK cells is restricted to altered self-cells. An activation receptor (AR) on NK cells interacts with its ligand on normal and altered self-cells, inducing an activation signal that results in killing. However, engagement of inhibitory NK cell receptors such as KIR and CD94/NKG2 by class I MHC molecules delivers an inhibitory signal that counteracts the activation signal. Expression of class I molecules on normal cells thus prevents their destruction by NK cells. Because class I expression is often decreased on altered self-cells, the killing signal predominates, leading to their destruction.

antibody together with macrophages to a culture of measles-infected cells. Similarly, cell-mediated killing of helminths, such as schistosomes or blood flukes, can be observed in vitro by incubating larvae (schistosomules) with antibody to the schistosomules together with eosinophils.

Target-cell killing by ADCC appears to involve a number of different cytotoxic mechanisms, but not complement-mediated lysis (Figure 14-15). When macrophages, neutro-phils, or eosinophils bind to a target cell by way of the Fc receptor, they become more active metabolically; as a result, the lytic enzymes in their cytoplasmic lysosomes or granules increase. Release of these lytic enzymes at the site of the Fc-mediated contact may result in damage to the target cell. In addition, activated monocytes, macrophages, and NK cells have been shown to secrete tumor necrosis factor (TNF), which may have a cytotoxic effect on the bound target cell. Since both NK cells and eosinophils contain perforin in cyto-plasmic granules, their target-cell killing also may involve perforin-mediated membrane damage similar to the mechanism described for CTL-mediated cytotoxicity.

A Lytic enzymes d Perforin O TNF

0 Granzymes

Eosinophil

Fc receptors

FIGURE 14-15

A Lytic enzymes d Perforin O TNF

0 Granzymes

Eosinophil

Fc receptors

Receptor Adcc

Ab bound to Ag and Fc receptor

Macrophage

Ab bound to Ag and Fc receptor

Macrophage

Antibody-dependent cell-mediated cytotoxicity (ADCC). Nonspecific cytotoxic cells are directed to specific target cells by binding to the Fc region of antibody bound to surface antigens on the target cells. Various substances (e.g., lytic enzymes, TNF, perforin, granzymes) secreted by the nonspecific cytotoxic cells then mediate target-cell destruction.

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