Regulatory T cells are crucial to proper immune system functioning. They are activated more slowly than killer and helper T cells, and put the brakes on the immune system once they are activated.

Efforts to study regulatory T cells have been hampered by the fact that their most specific marker, Foxp3, is located intracellularly, making it impossible to use as a marker. The combination of CD4 and CD25 is used most frequently to identify regulatory T cells, but is not entirely specific.

A paper published online in the May 15 Journal of Experimental Medicine described a new marker for regulatory T cells, which also has led to insights about its function.

That function also is still mysterious. Regulatory T cells are known to work partly through cytokine release, but blocking cytokines does not block the effects of regulatory T cells, suggesting that additional mechanisms exist.

In their JEM paper, the scientists more or less go from soup to nuts for regulatory T cells. "We have a marker for the [regulatory T] cells - even if you didn't know what the function was, you could purify them," senior author Simon Robson told BioWorld Today. "We have a biochemical signature - they generate adenosine. And we have a mechanism - they shut off T cells via the A2A receptor," an adenosine receptor on effector T cells. CD39 and CD73 are enzymes that remove the phosphate groups from ATP.

The overall effect, he added, is that the regulatory T cells "transform an environment from inflammatory to anti-inflammatory."

Robson, a professor of medicine at Harvard Medical School, and his colleagues first identified the combination of the surface proteins CD39 and CD73 as specific markers of regulatory T cells. CD39 knockout mice showed symptoms of consistent T cell activation, suggesting that the regulatory T cells were not able to inhibit effector T cells without CD39. In transplantation experiments, T cells lacking CD39 also were unable to prevent the rejection of skin grafts. Usually, such transplant tolerance is established by regulatory T cells' shutting off effector T cells.

Investigating the molecular mechanism by which CD39 helps shut off effector T cells, the researchers found that the regulatory T cells used CD39 and CD73 to generate adenosine from ATP and ADP. Adenosine can bind to and inactivate effector T cells - but only after about four to six days. Effector T cells do not express adenosine receptors earlier. Robson said that "few day's wait" before inactivation allows T cells to do their job, but then clamps down on them before inflammation can turn chronic.

Robson and his colleagues also recently have published work in the journal Diabetes showing that in blood vessels, CD39 acts as a protective factor that prevents excessive inflammation in diabetes. Diabetic CD39 knockout mice had more inflammation, as well as symptoms of kidney disease, than wildtype diabetic controls.

Robson believes that targeting CD39 has potential in a wide variety of disorders that have excessive inflammation as a cause or consequence: "Our hypothesis is that this is a unifying mechanism, in a way, for how adaptive mechanisms evolve from inflammation," he said.