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Immune Cells Can Simultaneously Stimulate And Inhibit Killer Cell Activity

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Dendritic cells, which are responsible for teaching other immune cells to attack infected or mutated cells, face a dangerous predicament. To demonstrate that an enemy has invaded, they must change to look a little bit like the invader. And once they look like an enemy, they risk being treated like one by their newly trained pupils. New research from Rockefeller University shows how the body’s immune system gets around this paradox by using simultaneous signals to both activate and inhibit a killer cell’s immune response.

Receptive party. Both activating (red) and inhibiting (green) receptors are present when dendritic cells synapse with natural killer cells. This dual setup teaches the natural killer cell to become aggressive while preventing it from attacking its dendritic cell instructor. (Credit: Image courtesy of Rockefeller University)

Natural killer cells, which serve as a critical line of defense against invaders, can only attack efficiently after dendritic cells have programmed them to turn aggressive. The immunity-directing dendritic cells bind to the natural killer cells in order to activate the “seek and destroy” receptors on their surface. The two types of cells then form a synapse through which they communicate.

Typically, these synapses consist of either activating or inhibitory receptors, allowing for the natural killer cells to be turned on or off. But when assistant professor Christian Münz, head of the Laboratory of Viral Immunobiology, and postdoc Fabienne Brilot looked closely at the structure of the synapse between natural killer and dendritic cells, they found that both receptor types were present but that they were segregated, each located in different areas of the synapse.

Their research describes an interaction that had never been seen before. “It’s a novel regulatory synapse,” Münz says. “It seems like inhibitory and activating domains are localized to the center of synapse and signal in parallel, mediating both activating and inhibitory signals.” The dendritic cells give different signals to the natural killer cells, inhibiting their cell-killing or “cytolytic” function while at the same time activating them to divide, emit signaling molecules called cytokines and transform into better killers.

How dendritic cells are able to spur other immune cells into action without getting destroyed in the process is a problem that relates not just to natural killer cells but also to T cells, which must also be activated to kill. The researchers are still just figuring out the basic biology of these synapses and plan to look next at naïve T cell activation. But ultimately, Münz says, what they’re finding could have implications for immune reactions that occur after organ transplantation. If they could find a way to prevent natural killer cells from recognizing dendritic cells, it might be possible to prevent the dendritic cells from activating the host’s immune system to attack the transplanted organ.

J. Clin. Invest. 117:3316-3329 (2007). doi:10.1172/JCI31751.
Copyright ©2007 by the American Society for Clinical Investigation

NK cell survival mediated through the regulatory synapse with human DCs requires IL-15R{alpha}
Fabienne Brilot, Till Strowig, Susanne M. Roberts, Frida Arrey and Christian Münz

Laboratory of Viral Immunobiology and Christopher H. Browne Center for Immunology and Immune Diseases, Rockefeller University, New York, New York, USA.

DCs activate NK cells during innate immune responses to viral infections. However, the composition and kinetics of the immunological synapse mediating this interaction are largely unknown. Here, we report the rapid formation of an immunological synapse between human resting NK cells and mature DCs. Although inhibitory NK cell receptors were polarized to this synapse, where they are known to protect mature DCs from NK cell lysis, the NK cell also received activation signals that induced mobilization of intracellular calcium and CD69 upregulation. The high-affinity component of the receptor for IL-15, IL-15R{alpha}, accumulated at the synapse center on NK cells, and blocking of IL-15R{alpha} increased NK cell apoptosis and diminished NK cell survival during their interaction with DCs. Furthermore, IL-15R{alpha}–deficient NK cells, obtained from donors with a history of infectious mononucleosis, showed diminished survival in culture with DCs. Synapse formation was required for IL-15R{alpha}–mediated NK cell survival, because synapse disruption by adhesion molecule blocking decreased DC-induced NK cell survival. These results identify what we believe to be a novel regulatory NK cell synapse with hallmarks of spatially separated inhibitory and activating interactions at its center. We suggest that this synapse formation enables optimal NK cell activation by DCs during innate immune responses.

Written by huehueteotl

November 14, 2007 at 1:21 pm

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