St. Jude scientists discover a signaling molecule that puts a stop to runaway immune responses

As any aficionado of exotic sports cars can attest, an automobile’s brake system is just as crucial as its acceleration potential. After all, a Ferrari hurtling along at 205 miles per hour needs an extremely effective braking system. Similarly, scientists at St. Jude Children’s Research Hospital have discovered an important signaling molecule that puts the brakes on a rogue immune response. The discovery could have applications for a host of autoimmune and inflammatory diseases, including type 1 diabetes, multiple sclerosis, Crohn’s disease and asthma. The finding could also have exciting ramifications for fighting cancer.

T cells are a type of white blood cell that play an important role in the body's immune response. Different kinds of T cells have drastically different functions. “Effector T cells mediate immune responses, like accelerators make cars go forward, while a specialized population called regulatory T cells stop an immune response like brakes slow down a car,” says Dario Vignali, PhD, of St. Jude Immunology.

Created in the thymus, a T cell (or T lymphocyte) is a type of white blood cell that helps protect the body against infection and disease. Effector T cells initiate and orchestrate the immune response. Regulatory T cells suppress or stop an immune response.

“Regulatory T cells actively suppress the activation of effector T cells that are reactive and damaging to self tissues, thereby preventing autoimmune disease.” explains Lauren Collison, PhD, a postdoctoral fellow in Vignali’s laboratory. “In the context of an infection, after the effector T cell has orchestrated the correct immune response and the pathogen is gone, regulatory T cells can help calm down the immune system.”

Vignali, Collison and their colleagues recently discovered that regulatory T cells release a protein complex called interleukin-35 (IL-35), which consists of two proteins. IL-35 is a cytokine, a chemical messenger protein that helps cells communicate with one another. The researchers also discovered that IL-35 acts as a brake on the aggressive effector T cells, a finding that, like a Ferrari itself, puts this cytokine in a class of its own. 

Scientists have identified more than 40 cytokines. Some act as accelerators; others as brakes. “The vast majority of cytokines are ‘go’ signals,” Vignali says. “In contrast, there are very few that issue ‘stop’ signals—only two or three—so IL-35 is special.’”

In fact, IL-35 is the only known cytokine that is made specifically by regulatory T cells and can directly suppress the activity of effector T cells.

“This discovery adds significantly to our understanding of how these cells prevent immune responses from running out of control and causing damage,” Vignali says. “To return to the car analogy, IL-35 may turn out to be a very important brake for the immune system.”

Forward and reverse

St. Jude immunologists look for ways to treat infections, cancer and other diseases by manipulating the immune system. People develop autoimmune diseases when the immune system becomes overactive. Evidence indicates that regulatory T cells are partially defective in a variety of these diseases. Vignali says novel treatments that add IL-35 or boost IL-35 activity may provide new therapeutic opportunities for autoimmune disorders by putting the brakes on the destructive attacks of the immune system. Such treatments may also help in inflammatory conditions such as asthma.

The situation may be reversed in many cancers. “There is mounting evidence that regulatory T cells stop our ability to eradicate tumors,” Vignali explains. “Tumors produce a dilemma within the immune system: On one hand, the system wants to get rid of the tumor cells, but on the other hand, they’re a part of us. Thus, regulatory T cells may prevent the immune system from attacking the tumor. Experimental studies have shown that if you can remove regulatory T cells or dampen their activity, then tumor immunity becomes vigorous, and the body can get rid of the tumor.”

A number of ongoing preclinical studies and clinical trials are studying drugs that block regulatory T cells, according to Vignali. These “brake” drugs could be combined with cancer vaccines to produce more effective therapies for certain types of cancer that can’t be treated by conventional approaches, such as chemotherapy and radiation. Cancer vaccines stimulate the immune system to recognize and attack specific targets, such as germs or cancer cells.

“Regulatory T cells are seen as a major impediment to the development of effective anti-cancer vaccines and may prevent sterilizing immunity in certain chronic infections, such as hepatitis C and tuberculosis,” Vignali says. “Blocking the activity of IL-35 may reduce the function of regulatory T cells and their ability to block anti-tumor immune responses. So treatments that block IL-35 activity may make anti-cancer vaccines more effective.”

Accelerating science

The discovery of IL-35 was chronicled in the November 2007 issue of the journal Nature. That’s a heady accomplishment for a young scientist like Collison, who arrived in Vignali’s lab less than two years ago.

“When I interviewed with Dario, he said the best thing about St. Jude is that your only limitation is your imagination, and he was right,” she says. “One of the best things about science is the fact that your discovery attracts the interest of other bright minds. Other scientists will hear about IL-35 and say, ‘Maybe this new protein is important in the disease process or condition that I’m studying.’ By collaborating with others whose expertise is different than ours, we can hasten progress.”

Collison is careful to keep her eyes on the ultimate goal: cures for children with cancer and other catastrophic diseases. “I believe this protein has a good chance of having therapeutic applications,” Collison says. “I’m a St. Jude donor myself, and like other donors, I think it’s important to remember that at the end of the day the goal of our research is to treat patients­—especially the children we have here at St. Jude.”

Reprinted from Promise Autumn 2007

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