September 25, 2003
Berkeley Lab Research News
Computer Simulations Point Way to New Finding About the Immune System
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BERKELEY, CA   Computer simulations, or experiments in silico, paved the way for subsequent genetic and biochemical experiments that yielded new information on how the body’s immune system gets sent into action. This new information has resolved a scientific controversy and holds therapetuic implications for autoimmunity.

This T cell (blue), one of the immune system’s principle means of defense, identifies the molecular signature of a dendritic cell (green) at a junction between the two called the immunological synapse. If the immunological synapse signals the presence of a foe, the T cell will attack.

Working with a custom-configured cluster of micro-computers at Lawrence Berkeley National Laboratory (Berkeley Lab) and cells derived from transgenic mice at Washington University School of Medicine, a multi-institutional team of scientists has shown that an intercellular junction called the “immunological synapse” controls the strength and duration of signals that can activate T cells, one of the body’s principle lines of defense against infections.

“We have found that the immunological synapse balances T cell receptor signaling and degradation, and if this adaptive control function goes awry, T cell activation will be misregulated,” says Arup Chakraborty, one of three corresponding authors of a paper published in the September 25, 2003 edition of Science Express. Chakraborty holds a joint appointment with Berkeley Lab’s Physical Biosciences and Materials Sciences Divisions, and both the Chemistry and Chemical Engineering Departments of the University of California at Berkeley. The other corresponding authors were Andrey Shaw of the Washington University Med School, and Michael Dustin of New York University (NYU).

Chakraborty, a pioneer of in silico experimentation for immunological research, is the first to capitalize on Berkeley Lab’s Scientific Cluster Support (SCS) program which was established to provide researchers with a cost-effective mid-range computing alternative to expensive supercomputers. Computer clusters consist of individual processors connected through Linux open-source software so that they perform as a single high-performance system. Through the SCS program, Chakraborty and his Berkeley research group were able to acquire and use an 84-processor cluster to accurately model the role of the immunological synapse in T cell signaling.

Berkeley scientist Arup Chakraborty has been a pioneer of in silico experimentation for immunological research.

“The results reported in this paper demonstrate how synergy between computational modeling and genetic, biochemical, and imaging experiments can solve important problems in cellular immunology,” says Chakraborty. “Our success should encourage further synergistic computational and experimental studies.”

Says William McCurdy, Associate Laboratory Director for Computing Sciences at Berkeley Lab, who initiated the SCS program, “This is the first example of a new kind of scientific support that Berkeley Lab is offering investigators. It is part of a continuing shift in our scientific culture towards more intensive use of computing in research.”

Computational models are ideal for studying complex phenomena with properties that emerge as a result of many linked variables. This describes the human immune system, an interdependent network of many different cell types that collectively protect our bodies from bacterial, parasitic, fungal and viral invaders, and against the growth of tumor cells. The process begins when markers on the surface of a cell called “antigens” identify the cell as “non-self.” In response, the cellular warriors of the immune system will attempt to engulf and kill the invader. Among these warriors are the lymphocytes (white cells) from the thymus, or T cells, whose appropriate activation is critical to a person’s health and well-being.

“T cells are the orchestrators of the adaptive immune response system,” explains Chakraborty. “They are responsible for reading the molecular signatures on cell surfaces, detecting the presence of pathogens and leading a counter-attack.”

The key to T cell activation is the information that passes between antigen-presenting cell surfaces and T cell receptors. This information is carried in a signal that must be enhanced and sustained long enough for the T cells to commit to mounting an immune response. The signal must also be cut off in time to avoid antigen-induced suicide or "apoptosis" of the T cells.

The most logical 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 synapses between communicating nerve cells. At this junction, a central cluster of T cell receptors surrounded by a sticky ring of adhesion molecules forms what NYU’s Dustin has described as a sort of “bull’s-eye.” While early in vitro studies supported the view that the immunological synapse enhances and sustains T cell receptor signaling, more recent in vitro studies carried out by Washington Med School’s Shaw indicated that signaling in the synapse was too short-lived (only a few minutes) to play any significant role.

“Because T cell signaling involves so many coupled events and there are so many competing forces, it was difficult to refute or assert either point of view,” says Chakraborty. “But by intertwining computational studies with genetic experiments, we were able to delineate the various effects and resolve the controversy.”

What Chakraborty and his group found when they ran simulations on their computer cluster is that the immunological synapse is indeed the site of enhanced T cell signaling but these triggered T cell receptors are subject to degradation over an extended period of time. This degradation, which eventually results in the signal being cut off, serves as a safeguard against antigen-induced T cell apoptosis.

The results of these in silico experiments, which Chakraborty carried out with assistance from UC Berkeley postdoctoral students Aaron Dinner and Subhadip Raychaudhuri, were passed onto Shaw and Dustin who were able to verify the computational model through specifically designed in vitro experiments using genetically engineered mouse cells.

“There is a competition between the triggering of T cell receptors due to antigens and the degradation of triggered T cell receptors,” says Chakraborty. “In the in vitro tests prior to our computational simulations, this competition was masking the fact that the immunological synapse is responsible for intense but self-limited T cell signaling.”

Chakraborty calls the findings on the immunological synapse reported in this paper “the tip of the iceberg” in terms of understanding exactly how T cells detect and respond to threats. It is a good demonstration, however, of what can be accomplished when the in silico approach to experimentation, a widely-accepted tool in the physical sciences, is used to complement genetic and biochemical experiments in the biological sciences.

“Tapping into this synergy is why Berkeley Lab formed its Physical Biosciences Division,” he says.

In addition to Chakraborty, Shaw and Dustin, other co-authors of the immunological synapse paper were Aaron Dinner and Subhadip Raychaudhuri of UC Berkeley, Kyeong-Hee Lee, Chun Tu, Richard Burack, Hui Wu, Julia Wang, Osami Kanagawa, Mary Markiewicz, Paul M. Allen of the University of Washington School of Medicine, and Gabriele Campi, Rajat Varma, and Tasha Sims of NYU.

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