Interesting research is being reported about by the Lawrence Berkeley National Laboratory and the University of California at Berkeley. With the help of the latest nanotechnologies, Berkeley scientists have created a novel platform to study the physiology of the T cell of the immune system. The research might have implications for the development of future treatments for autoimmune disorders, such as lupus or rheumatoid arthritis:
An experiment that began as a “fantasy pipe dream” just three years ago is now a reality. Researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California at Berkeley, combining nanotechnology with biochemistry, have created unique synthetic membranes that, for the first time ever, enable them to directly control signaling activity in living T cells from the immune system. Already their experiments have yielded surprising results…
It has also been established that the control center for T cell signaling is at the junction or point of contact between T cells and antigens, dubbed the “immunological synapse” because it resembles the synapse between two communicating nerve cells. At the immunological synapse, a central cluster of T cell receptors surrounded by a ring of adhesion molecules form what co-author Dustin has described as a sort of “bull’s-eye.” The center of this bull’s eye has been dubbed the “central supramolecular activation cluster,” or c-SMAC, because it was believed to be the source of T cell activation.
“The original idea behind the c-SMAC was that the larger the T cell receptor cluster, the stronger the T cell activation signal,” said Groves [Dr. Jay Groves, Berkeley Lab’s Physical Biosciences Division and UC Berkeley’s Chemistry Department -ed.]. “This simple vision of strength in numbers had begun to show cracks, and now we have demonstrated that just the opposite is true, the coalescence of the c-SMAC cluster extinguishes the T cell activation signal. The duration of the activation signal is related to the spatial organization of the T cell receptors rather than cluster size.”
Groves and his colleagues constructed their synthetic membranes out of lipids which they assembled onto a substrate of solid silica so that the membranes were able to float freely a few nanometers above the substrate. This enabled the researchers to preserve the membranes in their naturally fluid state, allowing lipids and T cell receptor proteins to diffuse and interact freely over macroscopic distances.
“The fluidity of our membranes created artificial antigen-presenting cell surfaces that enabled the formation of functional immunological synapses with living T cells,” said Groves.
Groves and his colleagues were able to spatially mutate the geometric shapes of the immunological synapses by embedding the silica substrate with chrome lines that were only 100 nanometers (about one ten-millionth of an inch) wide. These ultra-narrow chrome lines served as barriers that restricted the motion of membrane lipids and T cell receptor proteins. Using electron-beam lithography, the researchers were able to configure the chrome lines into several distinct patterns, including simple parallel lines, grids, and a series of concentric hexagons.
“By changing the shape of the immunological synapse, we showed that the synapse signal starts out in an amplified mode, and that the transport of the T cell receptors towards the center weakens and eventually extinguishes the signal, irrespective of the degree of clustering,” Groves said. “This may help explain why diseases of the autoimmune system are so difficult to treat. T cell receptor proteins do not respond like a conventional target, where if you hit the bull’s eye you trigger a signal. The spatial position of the receptor determines the type of signal it triggers.”.
In the picture from the press release: “This watercolor painting by Raghuveer Parthasarathy, a member of Jay Groves research group, shows a hybrid interface between a living T cell and a synthetic membrane on a substrate that has been patterned with chromium lines. T cell receptors (TCRs) are communicating with their corresponding signaling ligands on the membrane. By controlling the spatial arrangements of the signaling ligands, scientists can control the T cell’s overall response.”
The press release…
