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New insight into machinery of immune cells' 'tentacles'

Researchers have identified new molecular components of the machinery that regulates formation of the tentacle-like filaments by which immune system T cells grasp other cells. This embrace by such filaments is critical for the T cell to establish communication with cells called "antigen presenting cells" (APCs). Such communication enables the T cell to program itself to target invading microbes for destruction. Antigens are proteins in invading microbes that the immune system detects to trigger a counterattack.

The researchers said their findings of the machinery of formation of such "actin filaments" could offer targets for drugs to induce the immune system to work more effectively to fight infection; or to damp its stimulation in autoimmune disease.

Led by Duke University Medical Center pharmacologist Ann Marie Pendergast, the researchers published their findings in the Jan. 10, 2006, issue of Current Biology. The research was sponsored by the National Institutes of Health. Another paper in the same issue -- by Daniel Billadeau and colleagues of the Mayo Clinic College of Medicine -- confirmed the Duke researchers' findings and also implicated the same machinery in regulating calcium mobilization in T cells.

In their studies, Pendergast and her colleagues sought to discover the signaling proteins in T cells responsible for formation, or polymerization, of the protein actin into filaments following activation of the T cells. Such actin filament formation is crucial for the T cell to attach to APCs, called B cells, which collect and display foreign proteins from invading microbes.

The ensuing "conversation" between T and B cells enables the T cell to effectively identify and target such invaders for destruction. The site of contact between the T and B cells has been dubbed the "immunological synapse," because it is a communication link between the cells just as synapses between brain cells are the sites where one brain cell signals ano ther.

"It was known activation of the enzyme Rac was a key regulator of actin polymerization, but the downstream molecules in this pathway have remained elusive," said Pendergast. "The prevailing dogma was that this function is mediated by a protein called WASp. However, mice lacking WASp can still form immunological synapses, so we proposed that there was another unidentified pathway that regulated the process."

In their experiments, the researchers concentrated on a protein called "Abl interactor" (Abi), which had been identified earlier in the Pendergast laboratory. The earlier research had shown Abi to be an important adaptor protein in the signaling pathway involving a key cell regulatory enzyme called Abl. And Abl had already been shown to regulate remodeling of the cell's structure -- called the cytoskeleton -- that includes actin polymerization. Such remodeling is a key process in cellular growth and adaptation.

The researchers sought to understand whether the interaction between Abi and a complex of proteins that include the Wave family of proteins, might regulate actin polymerization. The Abi/Wave complex had already been shown to be involved in actin polymerization in other cells, said Pendergast.

Using tracer molecules to tag the proteins in T cells, the researchers found that both Abi and Wave homed in on sites of actin filament formation. What's more, when the scientists activated T cells with a "superantigen," they detected Abi at the contacts between T cells and B cells. Their experiments also revealed that the binding of Abi to Wave was required for Abi to reach the contact point.

The researchers' experiments also revealed that the Abi/Wave complex was naturally present in T cells. And when they knocked down the levels of either protein, the T cells lost the ability to polymerize actin at the immunological synapse.

Their experiments also revealed that, when T cells are stimulated, Abi recruits the Wa ve complex to the site of contact between T and B cells. They also found that mice lacking Abi proteins have a significant impairment in the immune system's production of a key immune cell trigger, called IL-2, in response to T cell activation. Additionally, mice deficient in Abi proteins have decreased T cell proliferation in response to activating stimuli, found the researchers.

"These findings add important new players in the regulatory pathway downstream of Rac," said Pendergast. "And since immune system activation depends critically on the formation of the synapse, these new players give us more targets for drugs to treat both immune deficiency and the hyperstimulation of the immune system in autoimmune disease."


Source:Duke University Medical Center

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