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12.3G: Natural Killer Cells (NK Cells)

 Skills to Develop

  1. Briefly describe how NK cells bind to and kill infected cells and tumor cells through ADCC.
  2. Briefly describe how NK cells recognize and kill infected cells and tumor cells that suppress MHC-I production.

NK cells are another group of cytolytic lymphocytes that are distinct from B-lymphocytes and T-lymphocytes, and participate in both innate immunity and adaptive immunity. NK cells are lymphocytes that lack B-cell receptors and T-cell receptors. They are designed to kill certain mutant cells and virus-infected cells in one of two ways:

Antibody-dependent Cellular Cytotoxicity

NK cells kill cells to which antibody molecules have attached through a process called antibody-dependent cellular cytotoxicity (ADCC) as shown in Figure 1, Figure 2, and Figure 3. The Fab portion of the antibody binds to epitopes on the "foreign" cell. The NK cell then binds to the Fc portion of the antibody. The NK cell is then able to contact the cell and by inducing a programmed cell suicide called apoptosis.

Destruction of Virus-Infected Cells by NK Cells through Antibody-Dependent Cellular Cytotoxicity (ADCC)

Step-1: The Fab portion of the antibody binds to epitopes on the "foreign" cell. The NK cell then binds to the Fc portion of the antibody. The NK cell is then able to contact the cell and release pore-forming proteins called perforins and proteolytic enzymes called granzymes. Granzymes pass through the pores and activate the enzymes that lead to apoptosis of the infected cell by means of destruction of its structural cytoskeleton proteins and by chromosomal degradation. As a result, the cell breaks into fragments that are subsequently removed by phagocytes. Perforins can also sometimes result in cell lysis.

Figure 1

Step 2: The Fab portion of the antibody binds to epitopes on the "foreign" cell. The NK cell then binds to the Fc portion of the antibody. The NK cell is then able to contact the cell and release pore-forming proteins called perforins and proteolytic enzymes called granzymes. Granzymes pass through the pores and activate the enzymes that lead to apoptosis of the infected cell by means of destruction of its structural cytoskeleton proteins and by chromosomal degradation. As a result, the cell breaks into fragments that are subsequently removed by phagocytes. Perforins can also sometimes result in cell lysis.

Figure 2

Step 3: NK cells release pore-forming proteins called perforins and proteolytic enzymes called granzymes. Granzymes pass through the pores and activate the enzymes that lead to apoptosis, a programmed suicide of the infected cell. Apoptosis occurs when certain granzymes activate a group of protease enzymes called caspases that destroy the protein structural scaffolding of the cell, degrade the cell's nucleoprotein, and activate enzymes that degrade the cell's DNA.

Figure 3

As a result, the infected cell breaks into membrane-bound fragments that are subsequently removed by phagocytes. If very large numbers of perforins are inserted into the plasma membrane of the infected cell, this can result in a weakening of the membrane and lead to cell lysis rather than apoptosis. An advantage to killing infected cells by apoptosis is that the cell's contents, including viable virus particles and mediators of inflammation, are not released as they are during cell lysis.

Innate Immunity

As discussed in Unit 5 under innate immunity, NK cells are also able to kill cells lacking MHC-I molecules on their surface. NK cells are important in innate immunity because they are able to recognize infected cells, cancer cells, and stressed cells and kill them. 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. For example, through cytokine production NK cells also suppress and/or activate macrophages, suppress and/or activate the antigen-presenting capabilities of dendritic cells, and suppress and/or activate T-lymphocyte responses.

NK cells use a dual receptor system in determining whether to kill or not kill human cells. When cells are either under stress, are turning into tumors, or are infected, various stress-induced molecules such as MHC class I polypeptide-related sequence A (MICA) and MHC class I polypeptide-related sequence B (MICB) are produced and are put on the surface of that cell.

The first receptor, called the killer-activating receptor, can bind to these stress-induced molecules, and this sends a positive signal that enables the NK cell to kill the cell to which it has bound unless the second receptor cancels that signal. This second receptor, called the killer-ihibitory receptor, recognizes MHC-I molecules that are usually present on all nucleated human cells. MHC-I molecules, produced by all nucleated cells in the body, possess a deep groove that can bind peptides from proteins found within the cytosol of human cells, transport them to the surface of that cell, and display the MHC-!/peptide complex to receptors on cytotoxic T-lymphocytes (CTLs). If the MHC-I molecules have peptides from the body's own proteins bound to them, CTLs do not recognize those cells as foreign and the cell is not killed. If, on the other hand, the MHC-I molecules have peptides from viral, bacterial, or mutant proteins bound to them, CTLs recognize that cell as foreign and kill that cell.

If MHC-I molecules/self peptide complexes are expressed on the cell, the killer-inhibitory receptors on the NK cell recognize this MHC-I/peptide complex and sends a negative signal that overrides the original kill signal and prevents the NK cell from killing the cell to which it has bound (Figure 4).

Figure 4: NK Cell Interacting with a Normal Body Cell. NK cells use a dual receptor system in determining whether to kill or not kill human cells. When cells are either under stress, are turning into tumors, or are infected, various stress-induced molecules are produced and are put on the surface of that cell. The first NK cell receptor, called the killer-activating receptor, recognizes these stress-induced molecules. This interaction sends a positive signal which enables the NK cell to kill the cell to which it has bound unless the second receptor cancels that signal. This second receptor, called the killer-inhibitory receptor, recognizes MHC-I molecules that are also usually present on all nucleated human cells. If MHC-I molecules are expressed on the cell, the killer-inhibitory receptor sends a negative signal that overrides the kill signal and prevents the NK cell from killing that cell.

Viruses, stress, and malignant transformation, however, can often interfere with the ability of the infected cell or tumor cell to express MHC-I molecules. Without the signal from the killer-inhibitory receptor, the kill signal from the killer-activating signal is not overridden and the NK cell kills the cell to which it has bound (Figure 5).

The NK cell then releases pore-forming proteins called perforins, proteolytic enzymes called granzymes, and chemokines. Granzymes pass through the pores and activate the enzymes that lead to apoptosis of the infected cell by means of destruction of its structural cytoskeleton proteins and by chromosomal degradation. As a result, the cell breaks into fragments that are subsequently removed by phagocytes (Figure 6). Perforins can also sometimes result in cell lysis.

In addition, NK cells produce a variety of cytokines, including proinflammatory cytokines, chemokines, colony-stimulating factors, and other cytokines that function as regulators of body defenses. For example, through cytokine production NK cells also suppress and/or activate macrophages, suppress and/or activate the antigen-presenting capabilities of dendritic cells, and suppress and/or activate T-lymphocyte responses.

Summary

  1. Natural Killer (NK) cells are able to recognize infected cells, cancer cells, and stressed cells and kill them. 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.
  2. NK cells play a role in adaptive immune responses by way of antibody-dependent cellular cytotoxicity or ADCC where they bind to and kill cells to which antibody molecules have bound.
  3. During ADCC, the Fab portion of the antibody binds to epitopes on the "foreign" cell. The NK cell then binds to the Fc portion of the antibody and the NK cell is then able to contact and kill the cell by inducing a programmed cell suicide called apoptosis.
  4. During innate immunity, NK cells use a dual receptor system in determining whether to kill or not kill human cells.
  5. When body cells are either under stress, are turning into tumors, or are infected, various stress-induced molecules are produced and are put on the surface of that cell.
  6. The first receptor, called the killer-activating receptor, can bind to these stress-induced molecules, and this sends a positive signal that enables the NK cell to kill the cell to which it has bound unless the second receptor cancels that signal.
  7. The second receptor, called the killer-ihibitory receptor, recognizes MHC-I molecules that are usually present on all nucleated human cells. If MHC-I molecules/self peptide complexes are expressed on the cell, the killer-inhibitory receptors on the NK cell recognize this MHC-I/peptide complex and sends a negative signal that overrides the original kill signal and prevents the NK cell from killing the cell to which it has bound.
  8. NK cells kill their target cells by inducing apoptosis, a programmed cell suicide.

Contributors

  • Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)