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Stanford Report, January 19, 2000

New role discovered for subset of T cells

BY KRISTIN WEIDENBACH

T cells are among the primary soldiers of the mammalian immune system, responsible for killing off cells that have been breached by foreign invaders like viruses and bacteria. Immunologists who study T cells have largely limited their attention to ab T cells -- named for the particular construction of the receptor molecule that juts out from the cell surface. These cells constitute 95 percent of the T cell population, and their job is to protect the body from dangerous microbes.

But immunologists have long believed that a population of T cells with an entirely different brief must exist -- cells whose role is to keep the immune system in check, counterbalancing over-stimulation of the system that could be dangerous to the body.

At the same time, a small group of T cells -- the gd variety, which constitute the remaining five percent of the T cell population -- have befuddled immunologists since the cells were discovered 14 years ago.

Now, Stanford researchers may have helped solve these two mysteries. Their latest results strongly support the notion that gd T cells help to regulate immune responses.

"Regulatory cells have always been proposed, and these cells have all the features that people would expect in a regulatory cell," said Yueh-hsiu Chien, PhD, associate professor of microbiology and immunology.

Chien says it was clear to scientists that ab and gd T cells contribute to defending the body in very different ways, and circumstantial evidence suggested that the function of gd T cells is geared toward regulation rather than immune response. "Their job is to maintain the homeostasis of the immune system," said Chien.

In some circumstances it is advantageous to shut down an immune response as soon as possible, Chien explained, because the body can be harmed by cytokines and other factors released by immune system cells activated to fight an infection. Septic shock is the most extreme example of overzealous immune system cells inadvertently damaging the body in their efforts to get rid of a bacterial infection. Auto-immune diseases such as rheumatoid arthritis and multiple sclerosis are other examples of bodily harm caused by an unruly immune system.

According to Chien, immunologists have theorized that the gd T cells help to maintain the balance of the immune system, but it was unclear exactly what they do and how they work. "In order to understand the function you need to know what these cells recognize," she said. And this was the question she and members of her lab set out to answer.

In a study published in the Jan 14 issue of Science, Chien and her colleagues showed that some gd T cells recognize a molecule called T22 and it's cousin T10. The researchers found that these molecules occur naturally on the surface of some white blood cells. It is not yet clear what happens once a gd T cell binds to one of these molecules, but the researchers discovered that the number of these "recognition molecules" on the surface of white blood cells increases when the cells become highly activated, such as during an immune response.

An exaggerated display of T22 and T10 molecules would divert the gd T cells toward an aspect of the immune system that may soon need dampening. In this way, the T22/T10 molecules can alert the gd T cells to "hot-spots" that have the potential to escalate into an over-vigorous immune reaction that risks harming the body if it is not contained.

The researchers estimate that about half of one percent of the gd T cells in a normal, healthy mouse specifically recognize and bind to the T22 molecule. It may sound like a very small number of cells, but the population is sizeable enough to impress immunologists. The researchers believe that the frequency of T10- and T22-specific gd T cells in normal mice is consistent with a regulatory function for these cells.

In an accompanying paper in the same issue of Science, Chien and her collaborators at the Scripps Research Institute in La Jolla, led by Ian Wilson, PhD, described the structure of T22. They found that, in accordance with the unique function of gd T cells, the shape of the recognition molecule is quite different from the molecules recognized by the more plentiful ab T cells. And, unlike the ab T cell recognition molecules, T22 has no requirement to simultaneously bind a piece of foreign protein such as a fragment of bacterium or viral shell. The structural features that the researchers revealed confirmed what members of the Chien laboratory had previously learned about the characteristics of T22 and add further weight to the theory that gd T cells are specialized for a task other than clearing dangerous microbes from the body.

The research at Stanford was funded by the National Institutes of Health, the National Science Foundation and the Katharine McCormick Foundation. SR