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Immunity in action
Rockefeller scientists capture the first-ever live images of immune system dendritic cells at work

If the immune system is an army, the lymph nodes are its field command centers. Located at pivotal traffic points throughout the body, they coordinate information sent back from immune system cells that circulate along the body’s periphery.
Now, in a series of experiments that has caused scientists to rethink some of their basic beliefs about how the cells of the immune system communicate with one another, Rockefeller’s Michel Nussenzweig, along with Michael Dustin of NYU Medical School, and colleagues have used genetic techniques and fluorescent microscopy to penetrate deep inside lymph nodes and visualize the activities of specialized components of the immune system called dendritic cells.
The work, which was published in the December issue of Nature Immunology, provides the research community’s first view, in real time, of the live actions of a network of dendritic cells that spend their entire lifespan inside the body’s lymph nodes.
Dendritic cells were discovered by Rockefeller scientists Ralph Steinman and Zanvil Cohn in 1973, and they play a special role in protecting the body from microbes and other potential threats, such as cancerous tumors. The dendritic cells’ long, spindly arms extend and retract in order to detect antigens. Once foreign material, or antigens, are detected, dendritic cells migrating throughout the body typically travel to the lymph nodes to use those same spindly arms, called processes, to inform other immune cells, the white blood cells called T and B cells, to take action.
But in addition to migratory dendritic cells, scientists now say there’s a network of dendritic cells that never leave the lymph nodes, and serve primarily to teach T and B cells what the body’s own tissues look like so that they will be safe in the event of an immune system emergency.
To visualize these stationary dendritic cells, the research team created laboratory mice genetically modified so that their dendritic cells produce a yellow fluorescent protein. The protein, coupled with a microscopic imaging technique that excites the fluorescent molecules with infrared light, creates perfect conditions for studying molecular activity in living systems.
“This imaging study has never been done before,” says co-first author Randall Lindquist, a Rockefeller University graduate student in Nussenzweig’s Laboratory of Molecular Immunology. “All of the other live microscopy experiments looking at dendritic cells in lymph nodes used cells that came from other sources and that were labeled with fluorescent dye.” Lindquist and his colleagues’ imaging technique preserves the immune system’s natural conditions to the fullest extent possible, and most closely represents how the immune system really works.
“It surprised us to see that this entirely different population of dendritic cells inside lymph nodes form what looks like a stationary network,” says Lindquist. “The network dendritic cells are just sitting there waving their processes. They’re not migrating.”
The much-studied mobile population of dendritic cells seems to interact with the stationary population, says Lindquist. In a related set of experiments, the researchers showed that transiting, mature dendritic cells can and do join the network, and they likely share their information across the network.
“Being able to watch dendritic cells in their natural state is valuable,” says Lindquist. If this network is teaching other immune cells to recognize, or tolerate, the body’s own tissues significant medical advances in the treatment of cancer and autoimmune diseases such as lupus may follow.
Already other research teams around the country are following in the Rockefeller-NYU team’s footsteps, and Nussenzweig, the university’s Sherman Fairchild Professor, predicts many new dendritic cell insights will emerge from noninvasive live-imaging techniques, such as the system he and his colleagues have developed.
Lindquist, Nussenzweig and their colleagues, too, are pursuing many new experiments based on what they’ve already learned. “The next thing we’d like to determine,” says Lindquist, “is how the network dendritic cells interact with T cells under conditions that induce tolerance or active immunity.”

January 28, 2005



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