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Link to original content: https://web.archive.org/web/20100727063451/http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/nkcell.html
I. THE INNATE IMMUNE SYSTEM
G. NATURAL KILLER (NK) CELLS
The overall purpose of this Learning Object is:
1) to learn the role of natural killer (NK) cells in innate immune defenses; and
2) to describe how type NK cells recognize and destroy certain virus-infected cells and cancer cells.
Innate immunity is an antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any microbe. This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.
Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPS and include LPS from the gram-negative cell wall, peptidoglycan and lipotechoic acids from the gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPS. (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)
Most body defense cells have pattern-recognition receptors for these common PAMPSand so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 of these microbial molecular patterns.
The innate immune responses do not improve with repeated exposure to a given infection and involve the following:
Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, and fever.
We will now take a closer look at natural killer (NK) cells.
G. Natural Killer (NK) Cells
NK cells are important in innate immunity because they are able to recognize infected cells, cancer cells, and stressed cells and kill them. They also secrete inflammatory cytokines (def) to promote an inflammatory response.
NK cells appear to use a duel 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 molecules such as MICA and MICB are produced and are put on the surface of that cell.
The first receptor, called the killer-activating receptor (def), can bind to various molecules such as MICA and MICB that are produced and are put on the surface of that cell, 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. 3).
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. 4).
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. 5). 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. Once activated, NK cells themselves produce large amounts of IFN-gamma to activate macrophages so they can kill ingested microbes.
NK cells also play a role in adaptive immune responses. As will be seen in Unit 5, NK cells are also capable of antibody-dependent cellular cytotoxicity or ADCC where they kill cells to which antibody molecules have bound.
