Still frames from a video of T cells interacting with GFP-labeled (green) antigen-presenting cells. Color overlaid on the cells highlights the intracellular calcium concentration of the T cells: Blue indicates low concentration; red is high.

Nothing in previous studies of NKT cells prepared the scientists for what they saw. Like other lymphocytes, NKT cells get pushed along by the blood's flow through the circulatory system. But inside the liver, their behavior is entirely different. The video images showed little self-propelled machines that crawled, amoeba-like, through the organ's tiny blood vessels. They moved swiftly yet seemingly at random, passing one another, changing direction, and even traveling against the flow of blood. Such apparently directionless, self-generated surveillance behavior—which continued until the NKT cells detected damage or infection and stopped in the vicinity of the problem to launch an immune response—had never before been observed.

NKT cells are believed to play an important role in inflammation and may be involved in triggering chronic hepatitis. Now, says Littman, armed with knowledge about their normal movement in the liver, “We need to get at the mechanistic aspects of the NKT cells' surveillance behavior. Can we manipulate it in disease systems?” Developing ways to regulate that behavior could potentially lead to treatments that reduce the inflammatory response in hepatitis and other liver diseases.

The surface proteins, or ligands, on an invading cell must dock in a key-in-the-lock fashion with the T cell's own surface receptors for the T cell to launch an immune response. But Davis, who gained wide attention two decades ago for identifying and cloning T-cell receptor genes for the first time, observed that the binding of just one or two receptor-ligand pairs was not enough to signal the mobilization of an immune response. Because the videos that Davis's laboratory produces are so exquisitely precise that a viewer can literally count how many ligands a T cell must “see” before it reacts, he and his colleagues were able to observe that it takes at least 3, and typically around 10 ligands, for the immune system to spring into action.

“In the long term, [quantifying such interactions] is the way to determine that a certain input creates certain consequences for a cell,” says Davis. “And you can only do this by imaging. That's how you get to the predictive power that has not been a part of cell biology before.” As director of Stanford's Institute on Immunity, Transplantation, and Infection, Davis hopes this newfound capability will yield tools to outsmart cancer cells, improve organ transplantation, and devise better vaccines.

Using a different imaging technology—positron emission tomography (PET)—to scan the immune system, HHMI investigator Owen N. Witte has also been able to visualize—and quantify—the generation of an immune response deep in the body. In his laboratory at the University of California, Los Angeles, Witte and his team used PET to detect radioactive chemical tracers in immune cells of mice with a solid tumor. The PET studies could track the immune response throughout the mice's bodies. T cells normally remain relatively inactive in lymph nodes, which serve as T-cell reservoirs, but in his PET studies, nodes even some distance from a tumor showed T-cell activity at least 10 times higher than normal levels.

Images: Davis Lab

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