The immune cell structure acts much like the iris in the eye, which adjusts to let vision function from very dark to very bright conditions, explains Michael Dustin, Ph.D., the Irene Diamond Associate Professor of Immunology at NYU School of Medicine, one of the study's lead authors. "If you're in a very dark room, you see by opening your iris and enhancing sensitivity to light," he explains. "But then if you get hit with a burst of light, momentarily you're blinded but then the system adapts, and that's like what the immune cells are doing in this process." This structure lets the body's immune system respond to signs of invasion over a huge range of magnitudes, he says.
Researchers are hopeful that now that the role of this channel of communication has been identified, it may serve as a potential target for treating diseases -- those in which the body attacks itself, such as in arthritis, as well as those in which the body doesn't recognize the attacker, such as tumors. "This could be the hidden factor in autoimmune disease," says Dr. Dustin.
The study was led by Dr. Dustin, Arup Chakraborty, Ph.D., Professor of Chemical Engineering and Chemistry at the University of California at Berkeley and faculty scientist at the Lawrence Berkeley National Laboratory, and Andrey Shaw, M.D., Professor of Pathology and Immunology at Washington University School of Medicine. Their findings are reported in the journal Science, which will be released online in the September 25 issue of Science Express ("The Immunological Synapse Balances T Cell Receptor Signaling and Degradation," K-H Lee et. al.; see (http://www.sciencexpress.org).
In order for the body's immune system to mount an attack on an invader, white blood cells have to go through a complex communication process with each other. Some present evidence of infection, called antigens, to T-cells, a special immune cell that determines if it should start an immune response. To facilitate this communication, the antigen-presenting cells and T-cells create a doughnut-shaped binding region between their membranes, which sticks them together. This region is called an immunological synapse, since it resembles the synapses that form between cells in the nervous system. The T-cell creates a concentration of binding sites, or receptors, for the antigen at the center of the synapse -- much like the center of a bull's eye target, explains Dr. Dustin.
Because of this concentration effect, it was first thought that the immunological synapse served to simply amplify signals between cells. But the team found in previous experiments that during the height of the immunological synapse formation, when the signaling should have been the strongest, there was only the merest trickle of signal. Most of the T-cell receptors were in fact being degraded -- in other words, ripped apart and recycled by the body -- which only happens after they've finished the majority of their signaling. "This created a kind of a shock to the field," recalls Dr. Dustin, "because everyone had been banking on this central cluster as a site of very active signaling."
To help solve the mystery of what the immunological synapse does, Dr. Chakraborty created a computer model portraying the flow of events that should occur in its formation. The model predicted that the immunological synapse does increase the strength of the signal to the T-cell receptors, but surprisingly, this also made the receptors much more likely to be degraded by the cell, which reduces the sensitivity of the T-cell to further incoming signal. "The model predicts that if you could turn off this degradation process," explains Dr. Dustin, "the T-cell would probably over-respond, and it would have a hard time attenuating these signals."
Simultaneously, and without knowing about the computer model, Dr. Shaw was working on genetically altered mice that were missing key proteins involved in forming the central cluster of the immunological synapse and in degrading T-cell receptors. The modified mice were indeed unable to form a well-organized immunological synapse, or degrade their T-cell receptors, so their T-cells over-responded to strong antigen signals. But Dr. Shaw's study was unable to show exactly why the defective T-cells weren't functioning correctly.
To decisively prove the connection between the two results, and conclusively demonstrate the function of the immunological synapse, Dr. Dustin's lab used a technology to allow these protein-modified cells to nonetheless form an immunological synapse, but still not degrade T-cell receptors. As predicted by Chakraborty's computer model, the center of the immunological synapse in these modified cells was opposite to normal cells – the signals were strong instead of weak. This showed that the immunological synapse can either augment signals or decrease them, depending on the situation.
"Together our three labs discovered that this structure is an adaptive control device, that is, it enhances the sensitivity of T-cells to antigen, but beyond a threshold it cuts off signaling to prevent T-cell death," explains Dr. Chakraborty.
"We only realized this with the use of a computational analysis that allowed us to see how all these different variables were playing out," added Dr. Shaw. "It's hard for most of us to imagine how this kind of union would work between computational biology and what I would call wet biology," he notes. "But this was a case where I really thought it was beautiful, it worked together so perfectly."
Dr. Dustin explains why such a range of sensitivity is necessary for the immune system: "In some cases, you have pathogens that, perhaps because they're trying to evade the immune response, won't generate many of these antigenic structures. So the T-cell has to be very sensitive to detect them," he says. "At the other extreme, in the evolution of these systems there was some pathogen that figured out that if it could swamp this system with one antigenic structure, it would just blind it. So the immunological synapse allows the system to adapt to very strong signals by reducing the T-cell receptor density, and then arrive at a uniform signaling rate in any situation."
Dr. Dustin notes that extra-strong antigen signals don't provide the immune system with any additional information about an invader. "Once the antigen level exceeds a very low threshold," he says, "the system should react to it on some level -- whether there's 10 of them or 10,000 or 100,000. It doesn't necessarily relate to the amount of the pathogen present; the immune system just wants to know whether there's something new to deal with."
In their next phase of research, Dr. Dustin hopes to figure out just what causes T-cell receptors to be degraded. In this process, the receptors are pulled inside of the cell, and sorted according to their signaling history: If they were part of intense signaling, they're degraded, but if not, they're returned to the surface. In addition, the cell is always making new T-cell receptors, at a slow but steady rate. What controls these processes is still unknown.
"One important thing about this study," says Mark Davis, Ph.D., professor of microbiology and immunology at the Stanford University School of Medicine, "is that it gives us some real clues as to what the function of the immunological synapse might be, and that's been a big question." Davis, an expert in this field who is familiar with this new study, adds that this research sheds light on some of the basic processes of the immune system. "Most of the time, when you are sick it's because your immune system is either doing too much or too little. As we learn more about the basics, it becomes obvious how to intervene and make things more sensitive or less sensitive." Such treatments, he notes, could lessen the severity of diseases in which the immune system mistakenly attacks its own tissues, as in arthritis or multiple sclerosis, and conversely, thwart those in which the body fails to eradicate or even notice an attacker, such as some tumors.
"The other thing that's important about this paper," adds Dr. Davis, "is that -- almost for the first time -- it's a marriage of theoretical biology, using a simulation, with real-time experimental biology. To me, that's a logical evolution of biology, and this is the most striking example I've seen. It's not something that's at all common right now, but it's where things should go."
NOTE TO EDITORS AND REPORTERS: Visuals of the immunological synapse are available from the NYU School of Medicine Office of Public Affairs.
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