I. THE INNATE IMMUNE SYSTEM
6. NATURAL KILLER (NK) CELLS AND INVARIENT NATURAL KILLER T-LYMPHOCYTES (iNKT 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.
3) to introduce the function of iNKT cells in immune responses.
LEARNING OBJECTIVES FOR THIS SECTION
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 and invarient natural killer T-lymphocytes (iNKT cells).
6. Natural Killer Cells (NK Cells) and Invariant Natural Killer T-Lymphocytes (iNKT Cells)
a. Natural Killer Cells (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. 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. 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.
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.
b. Invariant Natural Killer T-Lymphocytes (iNKT Cells) (def)
iNKT cells are a subset of lymphocytes that bridge the gap between innate and adaptive immunity. They have T-cell receptors (TCRs) (def) on their surface for glycolipid antigen recognition. They also have natural killer (NK) cell (def) receptors.
Through the cytokines (def) they produce once activated, iNKT cells are essential in both innate and adaptive immune protection against pathogens and tumors. They also play a regulatory role in the development of autoimmune diseases, asthma, and transplantation tolerance. It has been shown that iNKT cell deficiency or disfunction can lead to the development of autoimmune diseases, human asthma, and cancers.
Pathogens may not directly activate iNKT cells. The TCR of iNKT cells recognize exogenous glycolipid antigens (def), as well as endogenous self glycolipid antigens (def) presented by MHC-I-like CD1d molecules on antigen presenting dendritic cells (def). iNKT cells can also be activated by the cytokine interleukin-12 (IL-12) produced by dendritic cells that have themselves become activated by pathogen-associated molecular patterns (PAMPs) (def) of microbes binding to the pattern-recognition receptors (PRRs) (def) of the dendritic cell.
Once activated, the iNKT cells rapidly produce large quantities of cytokines, including interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-2 (IL-2), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), interleukin-13 (IL-13), and chemokines. Through the rapid productions of such cytokines, iNKT cells are able to promote and suppress different innate and adaptive immune responses. For example, large amounts of IFN-γ are produced by activated iNKT cells. IFN-γ activates NK cells and macrophages (def) as a part of innate immunity.
It has been proposed that if the iNKT cell is repeatedly stimulated by the body's own glycolipids in the absense of microbes that this might stimulate the iNKTcell /dendritic cell interaction to produce tolerizing signals that inhibit the TH1 cell response and possibly stimulate the production of regulatory T-lymphocytes (Treg cells). In this way it might suppress autoimmune responses and prevent tissue damage.
There is also growing evidence that early childhood exposure to microbes is associated with protection against allergic diseases, asthma, and inflammatory diseases such as ulcerative colitis. It has been found that germ-free mice have large accumulations of mucosal iNKT cells in the lungs and intestines and increased morbidity from allergic asthma and inflammatory bowel disease. However, colonization of neonatal germ-free mice with normal microbiota resulted in mucosal iNKT cell tolerance to these diseases. It has been proposed that microbes the human body has been traditionally exposed to from early childhood throughout most of human history might play a role in developing normal iNKT cell numbers and iNKT cell responses.
iNKT cells will be discussed in further detail in Unit 5.