Regulatory T Cells May Lull Immune Activators to Sleep

Caffeine, the world’s most relished drug, works in the brain by blocking the receptor for the sleep-inducing compound adenosine. It now appears that a recently discovered and hotly debated class of immune cells, the regulatory T cells, may take an opposite tack: producing adenosine for purposes of their own, namely, to quell other lymphocytes.

“Simplistically, one could say that these T regulatory cells, in generating adenosine, are putting T effector cells to sleep,” said Simon Robson. He and Terry Strom, both HMS professors of medicine in the Transplantation Center at Beth Israel Deaconess Medical Center, along with colleagues, report that adenosine production—and hence the T cells’ sleep-inducing effects—are the handiwork of two proteins found on the surface of the regulatory Ts. This is the first time the proteins, CD39 and CD73, have been identified on the surface of regulatory T cells. The findings, which appear in the May 14 Journal of Experimental Medicine, could lead to new approaches to identifying and understanding these elusive cells.

One of the big problems with regulatory T cell research is the lack of distinguishing features: the cells’ two main surface markers, CD4 and CD25, are found on other kinds of lymphocytes. Scientists have been searching for additional surface features. Robson and his colleagues had been studying how the ectoenzymes CD39 and CD73 help to quell clotting and inflammation in blood vessels. They knew the pair work hand in hand in endothelial cells to help produce extracellular adenosine. There were hints that CD39 might also play a role in the immune system, but it was not clear exactly how.

Using antibodies, Silvia Deaglio and Karen Dwyer, both HMS visiting assistant professors of medicine at BID, found the CD39 and CD73 markers were highly expressed on CD4+CD25+ T cells. Working with HMS instructor in medicine Wenda Gao, they confirmed that the ectoenzyme-bearing cells express other markers found on regulatory T cells and exhibit high levels of extracellular adenosine. The clincher came when the researchers cocultured separately the CD39-bearing cells and the CD39-knockout cells with T effector cells. Those bearing the CD39 protein suppressed T effector proliferation much more effectively.

Intriguingly, even the knockouts were able to suppress 50 percent of proliferation, suggesting that the CD39 adenosine-producing pathway is not the only suppressive mechanism in the regulatory T cell’s armamentarium, Robson said.

He and his colleagues also confirmed earlier work suggesting that adenosine is working on the effector cells through the A2A receptor. The findings could help open the door to new immune modulating therapies. “An A2A agonist could be used as an immune suppressant,” said Robson. “It may work to alleviate transplantation rejection, rheumatoid arthritis, inflammatory bowel disease, and other autoimmune conditions.”