Three immune signals share receptor.

Three reports now establish a common link among three key immune-system messengers. That link will help researchers make sense of how a single genetic defect can derail the body's defenses and how these messengers interact with one another, comments Thomas A. Waldmann at the National Cancer Institute in Bethesda, Md. "This is a big-league finding."

Certain cells release these messenger molecules, called interleukins, to regulate the growth, differentiation, or proliferation of immune-system white blood cells that defend the body against infections. Membranes of these target cells possess docking sites, or receptors, for the appropriate interleukins. The receptors often consist of several subunits, or chains, that combine to form the docking site and relay the interleukin's message.

In the Dec. 17 SCIENCE, two research groups show that to work well, at least three interleukins must use the same chain as part of their docking site. Because researchers discovered this chain first in the receptor for interleukin-2 (IL-2), it bears the name IL-2 receptor gamma chain. However, that chain makes cells listen also to the messages carried by interleukin-4 (IL-4) and interleukin-7 (IL-7), says Warren J. Leonard, a molecular immunologist at the National Heart, Lung, and Blood Institute (NHLBI), also in Bethesda, Md.

Scientists had known that people with a form of severe combined immune deficiency disease (SCID) that is linked to the X chromosome lacked this gamma chain. Such people make few or no white blood cells called T-cells. However, other kinds of SCID patients and SCID mice - both of which have the gamma chain but lack IL-2 - still make T-cells.

Thus, Leonard began to suspect that other messengers that stimulate T-cell production also depend on the IL-2 receptor's gamma chain. To test this idea, the NHLBI group genetically engineered lab-grown cells to contain the various receptors and subunits to be studied.

Masayuki Noguchi, who works with Leonard, studied IL-7, which typically stimulates the growth of immature T-cells in the thymus and affects the development of a different white cell, the B-cell.

Until now, scientists thought IL-7's docking site consisted of just one subunit. But these experiments show that while IL-7 does attach to that subunit, it fails to get into the cell unless the gamma chain is also present, Leonard says.

Then Sarah M. Russell of Leonard's group studied the role of this gamma chain in the function of IL-4. This interleukin regulates B-cells and also stimulates the growth of T-cells. As with IL-7, IL-4 binds to its receptor's lone subunit. However, IL-4 needs the gamma chain to cause enzymes inside the target cell to take on chemical side groups called phosphates, they note.

In a separate report, a Japanese team reaches similar conclusions about IL-4. Motonari Kondo and Kazuo Sugamura from Tohoku University School of Medicine in Sendai and their colleagues made antibodies that link to the gamma chain, thus blocking its binding by IL-2. They added these antibodies to different kinds of rodent cells growing in the laboratory and observed that the antibodies inhibited the growth-stimulating activity of both IL-2 and IL-4.

"[All these results] really allow us to better understand why it is that children with [X-linked] SCID have the profound immune deficiencies that they have," says Leonard.

"Any error to gamma means you can't make any response to IL-2, IL-4, and IL-7. You lose [almost] everything," Waldmann adds.

Moreover, "Now people will have to think about how one signal can interfere with another signal," says Gerard Zurawski at DNAX Research Institute in Palo Alto, Calif. These interleukins may compete for the available gamma chains.

For example, the Japanese group calculates that its cells each possess about 2,800 gamma chains, nearly all of which become unavailable when the scientists add IL-2, leaving none for IL-4. In contrast, only about 1,200 gamma chains are tied up when the researchers expose a cell to lots of IL-4. Even so, those cells become less responsive to IL-2, says Sugamura.