New Light Shed Upon T and B Cell Interactions

[Guest guest]

Duke University Medical Center

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

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 another.

" 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 Wave 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. "

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Besides Pendergast, other co-authors were Witherow, Jing Gu,

Chislock and Colleen Ring -- in the Pendergast laboratory

in the Department of Pharmacology and Cancer Biology. Co-author

Zipfel is in the Duke Medical Center Department of Surgery.

Bunnell of the Tufts University School of Medicine also was a

co-author.