Roles of Natural Killer Cells in Body Defense
Natural Killer Cell Interacting with a Normal Body Cell Expressing MHC-I Molecules
Natural Killer Cell Interacting with a Virus-Infected Cell Not Expressing MHC-I Molecules
Natural-Killer-Cell-Induced Apoptosis of a Virus-Infected Cell
Natural-Killer-Cell-Induced Antibody-Dependent Cellular Cytotoxicity of a Virus-Infected Cell
This series of animations illustrate how natural killer (NK) cells are able to recognize and induce the killing of certain infected cells, cancer cells, and stressed cells by using a dual receptor system, as well as by way of antibody-dependent cellular cytotoxicity.
NK cells are important in both innate and adaptive immunity. They are able to recognize and induce the killing of certain infected cells, cancer cells, and stressed cells. In addition, they produce a variety of cytokines, including proinflammatory cytokines, chemokines, colony-stimulating factors, and other cytokines that function as regulators of body defenses, including suppressing and/or activating macrophages, suppressing and/or activating the antigen-presenting capabilities of dendritic cells, and suppressing and/or activating T-lymphocyte responses (2).
NK cells use a dual receptor system in determining whether to kill or not kill human cells to which they bind. These dual receptors are termed the killer activating receptor (KAR) and the killer inhibitory receptor (KIR).
When cells are either under stress, developing into tumors, or infected, various stress-induced molecules, such as heat shock proteins, extracellular matrix fragments, and altered membrane phospholipids, are produced and expressed on the surface of those cells. To start the killing process, KARs on the surface of the NK cell are able to recognize the various stress-induced molecules on the target cell's surface and binding to these molecules sends a positive signal that enables the NK cell to induce the death of the cell to which it has bound unless a KIR cancels that signal (1, 2).
This KIR typically recognizes major histocompatibility complex class I (MHC-I) molecules that are usually present on all nucleated human cells. If sufficient numbers of MHC-I molecules with bound self-peptides are expressed on the cell, the KIRs on the NK cell recognize these MHC-I–peptide complexes and trigger a negative signal that overrides the original kill signal (1, 2).
Infection, malignant transformation, and other forms of cellular stress, however, can often interfere with the ability of the infected cell or tumor cell to express MHC-I molecules. The stress can also up-regulate the production of stress-induced molecules. Without the signal from the KIRs, the kill signal triggered by the KAR is not overridden and the NK cell induces the death of the cell to which it has bound (1, 2).
NK cells are also capable of antibody-dependent cellular cytotoxicity or ADCC, during which they kill cells to which antibody molecules have bound. NK cells have cluster of differentiation (CD) molecules known as CD16 on their surface that function as receptors for the fragment, crystallizable ( Fc ) portion of the antibody isotype immunoglobulin G (IgG). When IgG is made against epitopes on "foreign" membrane-bound cells, such as virus-infected cells and cancer cells, the fragment, antigen-binding ( Fab ) portions of the antibodies react with the foreign cell. The CD16 receptors on the NK cells then bind to the Fc portion of the antibodies and induce apoptosis of that cell (1).
Macromedia Flash Professional 8 was used in constructing this animation. Illustrations were drawn using Adobe Illustrator 10.0.3 and imported into Flash Professional 8.
Slide 1 shows a normal but stressed cell producing low levels of stress-induced molecules in addition to MHC-I molecules displaying normal self-peptides.
Slides 2 and 3 illustrate an NK cell using its killer activating receptor to bind to a normal human cell displaying stress-induced molecules. This interaction sends a positive signal that enables the NK cell to induce the death of the cell to which it has bound unless a killer inhibitory receptor cancels that signal.
In slides 4 and 5, an NK cell is shown using its killer inhibitory receptor to bind to MHC-I molecules with bound self-peptides on the target cell. When MHC-I–self-peptide complexes are expressed on the cell, the killer inhibitory receptors on the NK cell send a negative signal that overrides the original kill signal and prevents the NK cell from inducing the death of the cell to which it has bound.
In slides 1 and 2, a virus-infected cell is shown displaying high levels of stress-induced molecules but no MHC-I molecules.
Slides 3 and 4 illustrate an NK cell using its killer activating receptor to bind to a virus-infected cell displaying stress-induced molecules. This interaction sends a positive signal that enables the NK cell to induce the death of the cell to which it has bound unless a killer inhibitory receptor cancels that signal.
Slides 5, 6, and 7 show the killer inhibitory receptor of the NK cell unable to detect MHC-I molecules on the infected cell. Without the signal from the killer inhibitory receptor, the kill signal triggered by the killer activating receptor is not overridden and the NK cell induces the death of the cell to which it has bound.
Slides 8 to 11 show the NK cell releasing pore-forming proteins called perforins and proteolytic enzymes called granzymes. Granzymes pass through the pores and activate the caspase enzymes that lead to apoptosis, a programmed cell suicide of the infected cell.
Slides 1 and 2 show protease enzymes called caspases destroying the protein structural cytoskeleton of the cell, degrading the cell's nucleoprotein, and activating enzymes that degrade the cell's DNA. As a result, the infected cell breaks into membrane-bound apoptotic fragments.
In slides 3 and 4, a phagocyte is shown engulfing and destroying the apoptotic fragments. Killing the infected cell by apoptosis reduces inflammation and also precludes the release of viruses that have assembled within the infected cell preventing their spread to other cells.
Slide 1 shows a virus-infected cell displaying viral epitopes. Also shown are labeled molecules of the antibody IgG produced against those viral epitopes.
Slide 2 shows the Fab portion of the IgG binding to the viral epitopes on the virus-infected cell.
Slides 3 and 4 show an NK cell using its Fc receptor to bind to the Fc portion of the cell-bound IgG.
Slides 5 to 8 show the NK cell releasing pore-forming proteins called perforins and proteolytic enzymes called granzymes. Granzymes pass through the pores and activate the caspase enzymes that lead to apoptosis, a programmed cell suicide of the infected cell.
1. Abbas AK, Lichtman AH, and Pillai S. 2007. Cellular and molecular immunology, 6th ed, p 38–42, 255–257, 315–319, 328–329. Saunders/Elsevier Publishing, Philadelphia, PA.
2. Vivier E, et al . 2011. Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49.