Wise Young
02-14-2007, 11:56 PM
About three decades ago, scientists identified a special type of cells called "natural killer t-cells". These NK cells appeared to be able to attack and kill tumor cells without having been sensitized to the cells. At first, their presence was controversial but the availability of monoclonal antibody against specific surface antigens on NK cells made identification of the cells very easy and everybody accepted their existence.
Further research showed that NK cells are tightly regulated (as you might expect for cells capable of murder without provocation) and require interferon alpha/beta activation, as well as interleukin-2 and interferon gamma (Source (http://en.wikipedia.org/wiki/Natural_killer_cell)). They also have an Fc receptor. Fc is the constant part of antibodies. In other words, antibodies (any type) will activate NK cells. In humans, NK cells express CD16 and CD56. Certain strains of mice express NK1.1/NK1.2.
NK cells express several activating and inhibiting receptors that regulate their activities. These include inhibitory receptors that detect MHC class I antigens. In other words, the NK cells are inactivated or inhibited in the presence of cells that express MHC antigens. Another series of names for such antigens are human leukocyte antigen (HLA) that the immune system uses to detect non-self (foreign) cells. So, NK cells express CD94 or NKG2 which detects MHC I molecules like HLA-E. They also express Ly49 that is a receptor for MHC I molecules. They express KIR (Killer Cell Immunoglobulin-like Receptors) that are the main receptors for class MHC I (HLA-A, HLA-B, and HLA-C) antigens, as well as HLA-G.
Please note that these HLA receptors are inhibitory. In other words, NK cells are inactivated or inhibited by the presence of MHC antigens. They should not play a major role in immune rejection of cells that express HLA antigens. This is most interesting indeed because there are certain cells that are believed not to express all the HLA antigens and are therefore "immune-privileged". For example, embryonic stem cells have been claimed to be immune to rejection. Likewise, adult mesenchymal stem cells have also been said to be immune to rejection. Umbilical cord hematopoeitic cells have been said to be more immune-privileged than bone marrow cells, such that only 4/6 HLA matches will suffice for engraftment of 80% of umbilical cord blood transplants whereas 6/6 HLA matches is necessary for such a higher percentage of engraftment.
One recent series of studies described in the Scientist (Source (http://www.the-scientist.com/article/home/43702/)) have now yielded new insights into what NK cells do. NK cells express a receptor called CD1d which, until recently, was thought to bind only one antigen (an obscure lipid antigen called alpha-Gal-Cer found in marine sponges). Nobody knew why NK cells would have a receptor to these antigens. Who knows, perhaps these marine sponges posed to our survival in the past? What the studies showed was that the CD1d receptor recognized alpha-linked lipids from endosomes and lysosomes of lymphoid organs.
This discovery is likely to open vast possibilities of understanding NK cell function. For example, NK cells constitute 60% of the cells found in asthmatic lungs and it was not clear why. Likewise, there are NK cells in the spinal cord after injury. Now that the door is open to the possibility of alpha-linked lipid antigens, NK cells may be designed to respond to lipid antigens that are presented by cancer cells (and possibly stem cells). They may play an important role in immune rejection of cells transplanted to the spinal cord.
NK cells may play a role in long-term rejection. For example, Itescu, et al. (1998) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9619766&dopt=Abstract) studied pig-to-primate cardiac xenografts and found the xenografts to be invaded by NK cells and macrophages at 3-4 days. The NK cells kill the porcine grafts by antibody dependent cellular cytotoxicity and lymphokine activity. The main signal appears to be IL-2.
Prevention of NK cell activation is likely to be a critical component of preventing immune rejection of transplanted stem cells. One of the most common form of foreign cell transplant in a person is a pregnancy. After all, the trophoblasts that attach to the maternal uterus are foreign cells. Likewise, the fetus is of course foreign. Eriebacher, et al. (2002) (http://www.pnas.org/cgi/reprint/99/26/16940.pdf) showed that trophoblasts are rapidly rejected when they are injected into the blood stream of mice. However, they appear to be protected against immune rejection in the uterus. Understanding how the uterus does will be key to protecting allogenic cell transplants from immune rejection.
In summary, NK cells are murderous cells that respond to interferons or macrophage-derived cytokine signals to kill. In other words, they are like shock troops brought in with macrophages to areas of inflammation and are turned on by macrophages. It is, however, of great interest that NK cells possess receptors that turn them off if they encounter classical MHC antigens that turn on immune-responses to foreign cells. In other words, they appear to be forbidden to kill cells that express classic immune antigens. If so, they may play a greater role in killing cells that do not express MHC antigens, such as embryonic stem cells, mesenchymal stem cells, and umbilical cord blood cells. Finally, recent work suggest that NK cells respond to alpha-linked glycolipids which are part of lysozymes. Understanding how the body regulates NK cells will be crucial to developing methods to prevent immune rejection of transplanted stem cells.
Wise.
Further research showed that NK cells are tightly regulated (as you might expect for cells capable of murder without provocation) and require interferon alpha/beta activation, as well as interleukin-2 and interferon gamma (Source (http://en.wikipedia.org/wiki/Natural_killer_cell)). They also have an Fc receptor. Fc is the constant part of antibodies. In other words, antibodies (any type) will activate NK cells. In humans, NK cells express CD16 and CD56. Certain strains of mice express NK1.1/NK1.2.
NK cells express several activating and inhibiting receptors that regulate their activities. These include inhibitory receptors that detect MHC class I antigens. In other words, the NK cells are inactivated or inhibited in the presence of cells that express MHC antigens. Another series of names for such antigens are human leukocyte antigen (HLA) that the immune system uses to detect non-self (foreign) cells. So, NK cells express CD94 or NKG2 which detects MHC I molecules like HLA-E. They also express Ly49 that is a receptor for MHC I molecules. They express KIR (Killer Cell Immunoglobulin-like Receptors) that are the main receptors for class MHC I (HLA-A, HLA-B, and HLA-C) antigens, as well as HLA-G.
Please note that these HLA receptors are inhibitory. In other words, NK cells are inactivated or inhibited by the presence of MHC antigens. They should not play a major role in immune rejection of cells that express HLA antigens. This is most interesting indeed because there are certain cells that are believed not to express all the HLA antigens and are therefore "immune-privileged". For example, embryonic stem cells have been claimed to be immune to rejection. Likewise, adult mesenchymal stem cells have also been said to be immune to rejection. Umbilical cord hematopoeitic cells have been said to be more immune-privileged than bone marrow cells, such that only 4/6 HLA matches will suffice for engraftment of 80% of umbilical cord blood transplants whereas 6/6 HLA matches is necessary for such a higher percentage of engraftment.
One recent series of studies described in the Scientist (Source (http://www.the-scientist.com/article/home/43702/)) have now yielded new insights into what NK cells do. NK cells express a receptor called CD1d which, until recently, was thought to bind only one antigen (an obscure lipid antigen called alpha-Gal-Cer found in marine sponges). Nobody knew why NK cells would have a receptor to these antigens. Who knows, perhaps these marine sponges posed to our survival in the past? What the studies showed was that the CD1d receptor recognized alpha-linked lipids from endosomes and lysosomes of lymphoid organs.
This discovery is likely to open vast possibilities of understanding NK cell function. For example, NK cells constitute 60% of the cells found in asthmatic lungs and it was not clear why. Likewise, there are NK cells in the spinal cord after injury. Now that the door is open to the possibility of alpha-linked lipid antigens, NK cells may be designed to respond to lipid antigens that are presented by cancer cells (and possibly stem cells). They may play an important role in immune rejection of cells transplanted to the spinal cord.
NK cells may play a role in long-term rejection. For example, Itescu, et al. (1998) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9619766&dopt=Abstract) studied pig-to-primate cardiac xenografts and found the xenografts to be invaded by NK cells and macrophages at 3-4 days. The NK cells kill the porcine grafts by antibody dependent cellular cytotoxicity and lymphokine activity. The main signal appears to be IL-2.
Prevention of NK cell activation is likely to be a critical component of preventing immune rejection of transplanted stem cells. One of the most common form of foreign cell transplant in a person is a pregnancy. After all, the trophoblasts that attach to the maternal uterus are foreign cells. Likewise, the fetus is of course foreign. Eriebacher, et al. (2002) (http://www.pnas.org/cgi/reprint/99/26/16940.pdf) showed that trophoblasts are rapidly rejected when they are injected into the blood stream of mice. However, they appear to be protected against immune rejection in the uterus. Understanding how the uterus does will be key to protecting allogenic cell transplants from immune rejection.
In summary, NK cells are murderous cells that respond to interferons or macrophage-derived cytokine signals to kill. In other words, they are like shock troops brought in with macrophages to areas of inflammation and are turned on by macrophages. It is, however, of great interest that NK cells possess receptors that turn them off if they encounter classical MHC antigens that turn on immune-responses to foreign cells. In other words, they appear to be forbidden to kill cells that express classic immune antigens. If so, they may play a greater role in killing cells that do not express MHC antigens, such as embryonic stem cells, mesenchymal stem cells, and umbilical cord blood cells. Finally, recent work suggest that NK cells respond to alpha-linked glycolipids which are part of lysozymes. Understanding how the body regulates NK cells will be crucial to developing methods to prevent immune rejection of transplanted stem cells.
Wise.