Scientists have long known that T cells play a major role in orchestrating the body’s immune response. But researchers have been unsure exactly how these cells send and receive signals to attack invaders.
One fundamental question has been whether it is the number or the pattern of receptors on the surface of the T cell that controls the response. Understanding this cellular language could, for example, help researchers design better treatments for auto-immune diseases, such as allergies or rheumatoid arthritis, where the immune system has sent a misguided message to attack itself.
In a new experiment, published last week in Science, Jay Groves and colleagues at the University of California at Berkeley designed an artificial membrane that allows them to begin to answer these questions. The membrane has proteins that are constricted in a specific region. When receptors on the T cell bind to the proteins on the artificial membrane, the receptors are constrained to these specific geometric patterns, allowing a closer examination of the effects of the patterns.
Under normal physiological conditions, when a T cell binds to an infected cell, receptors on the surface of the T cell migrate toward the junction between the two cells. Previously, scientists thought that the growing number of receptors triggered a strong T cell activation. But when Grove and his team blocked the migration of T cell receptors by binding them to locked-in proteins on the artificial membrane, which acts like an infected cell, they discovered it was the position of the receptor that actually controlled the response.
“Spatial configuration matters rather than number,” says Groves. “It’s like realizing when reading a sentence you need to pay attention to the order of the letters to know what the words mean, you can’t just count the number of each kind of letter.”
To develop the artificial membrane, the Berkeley researchers used electron beam lithography to create nanoscale chrome patterns on a silica substrate, which was then coated with membrane lipids and proteins. Although the proteins normally float freely through the lipid membrane, on the synthetic membrane, they’re kept in place by the chrome patterns, which act as barriers.
Other experts say these findings demonstrate the power of nanotechnology for studying cellular processes. “This paper represents a wonderful, rare, and early example of how bringing together micropatterning technology and cell biology can help shed light on interesting questions in biology,” says Arup K. Chakraborty, a theoretical immunologist at MIT.
The technology eventually could be used to develop cell-based drug screens in order to determine how candidate compounds affect immune-cell signaling. For example, scientists could expose cells bound into an artificial membrane to different drugs, and observe how those drugs affect T cell clustering. “Understanding how [cell signaling] works is a big component of learning how to control it with drugs,” says Groves.
The findings could also lead to new treatments for auto-immune diseases, in which the immune system attacks the body’s own proteins. “Effective treatments for auto-immune diseases like Rheumatoid arthritis turn down immune response, but this leaves the patient more vulnerable to infection,” says Michael Dustin, an immunologist at the Skirball Institute of Biomolecular Medicine at New York University, who collaborated on the Berkeley project. “You could use patterned particles to make more specific treatments, but first we need to learn the language.”
Once researchers experimentally determine the signals associated with different patterns, it may be possible to build a particle with pre-patterned receptors that direct T cells to turn off the immune response, says Dustin. If the pattern was specific enough to turn off the immune response in particular organs, such as the brain in multiple sclerosis or the joints in rheumatoid arthritis, the rest of the immune system could still function effectively to fight viral invaders.
The technique also has blue-sky applications, going far beyond the immune system. “If you can make artificial surfaces that communicate with cells on a sophisticated level, you could make devices that tell cells what to do,” says Groves. “You could get cells to generate energy or do a chemical conversion; it would be tremendous.”