III. THE ADAPTIVE IMMUNE SYSTEM
B. MAJOR CELLS AND KEY CELL-SURFACE MOLECULES INVOLVED IN ADAPTIVE IMMUNE RESPONSES
7. Natural Killer Cells (NK Cells)
The overall purpose of this Learning Object is to introduce the role of NK cells in adaptive immune responses.
Adaptive (acquired) immunity refers to antigen-specific defense mechanisms that take several days to become protective and are designed to remove a specific antigen (def). This is the immunity one develops throughout life. There are two major branches of the adaptive immune responses: humoral immunity and cell-mediated immunity.
1. humoral immunity (def): humoral immunity involves the production of antibody molecules in response to an antigen (def) and is mediated by B-lymphocytes.
2. cell-mediated immunity (def): Cell-mediated immunity involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen (def) and is mediated by T-lymphocytes.
We will now take a look at NK cells.
7. NK Cells
NK cells are another group of cytolytic lymphocytes, distinct from B-lymphocytes (def) and T-lymphocytes (def), that participate in both innate immunity and adaptive immunity. NK cells are lymphocytes that lack B-cell receptors (def) and T-cell receptors (def). They are designed to kill certain mutant cells and virus-infected cells in one of two ways:
1. NK cells kill cells to which antibody molecules (def) have attached through a process called antibody-dependent cellular cytotoxicity (ADCC) as shown in Fig. 1, Fig. 2, and Fig. 3 . The Fab portion (def) of the antibody binds to epitopes on the "foreign" cell. The NK cell then binds to the Fc portion (def) of the antibody. The NK cell is then able to contact the cell and by inducing a programmed cell suicide called apoptosis (def).
2. As discussed in Unit 4 under innate immunity, NK cells are also able to kill cells lacking MHC-I molecules (def) 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 (def), including proinflammatory cytokines (def), chemokines (def), colony-stimulating factors (def), and other cytokines that function as regulators of body defenses. For example, through cytokine production NK cells also suppress and/or activate macrophages (def) , suppress and/or activate the antigen-presenting capabilities of dendritic cells (def), and suppress and/or activate T-lymphocyte (def) 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 (def), 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 (def), recognizes MHC-I molecules (def) 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 or CTLs (def). 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. (CTLs will be discussed in greater detail in Unit 5.)
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 (see Fig. 4).
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 (see Fig. 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 (see Fig. 6). Perforins can also sometimes result in cell lysis.
Cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) produced by TH1 lymphocytes activate NK cells.
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