Weill Cornell's Ma identifies mechanism governing immune system suppression

By Ernie J. Mundell

Researchers at Weill Cornell Medical College in New York City believe they have uncovered a molecular switch that naturally suppresses the body's immune response in situations where it's not needed. Drugs that mimic or oppose this mechanism might someday fight autoimmune disorders like lupus or rheumatoid arthritis, or protect immune cells from enemies like HIV.

Ma

"It has real implications for infectious diseases, where you want improved immunity, and also autoimmune diseases, where you don't want such a strong immune response. It works both ways," said lead researcher Xiaojing Ma, M.D., an associate professor in Weill Cornell's Department of Microbiology and Immunology. His research group's findings were published in the Nov. 17 issue of the journal Immunity.

When bacteria, viruses or other invaders threaten cells, compounds called pro-inflammatory cytokines produced by the infected cells send out chemical signals that alert immune T cells to ready themselves for battle. T cells are primed to recognize "the enemy" by the presence of specific molecules, called antigens. (T cells, one of the five kinds of white blood cells, or leukocytes, are so named because they mature in the thymus.)

However, scientists have long puzzled over the fact that in some cases T cells can remain dormant, even in the presence of these antigens. "That's definitely what happens when the body's own cells die a natural death, through apoptosis -- programmed cell death," Ma said.

When cells reach the end of their natural lifespan, immune white blood cells called macrophages act as the main disposal units, "eating up" dead or dying cells. Even though the macrophage releases antigens during this cleanup, T cells keep quiet.

"That's a good thing, because you wouldn't want a big immune response in this case, triggering inflammatory symptoms such as aches and fever," Ma said.

In fact, runaway immune systems are the very heart of painful chronic conditions such as lupus, rheumatoid arthritis and inflammatory bowel diseases like Crohn's. Scientists have been looking for decades for a way to short-circuit the immune response as a means of easing these conditions.

The Weill Cornell researchers discovered that "even though the activated macrophage presents the proper antigens as it eats up dead or dying cells, one particular pro-inflammatory cytokine, called interleukin 12 (IL-12) is not produced," according to Ma. IL-12 is a major factor that activates lymphocytes such as Natural Killer (NK) and T cells to fight off infection and eliminate cancerous cells. Without IL-12, cell-mediated immune responses are suppressed.

Digging deeper, the researchers discovered that cell-to-cell contact between the macrophage and the dying cell activates a novel protein called GC-binding protein (GC-BP), "possibly through a specific receptor on the macrophage's surface," Ma said. GC-BP then undergoes a chemical change that allows it to enter into the nucleus of the macrophage.

Once there, the protein targets and switches off the gene responsible for IL-12 production.

The result: macrophage activity with suppressed immune response. "We studied this in mouse and human cells, and it works the same way," Ma said. "We were the first to identify GC-BP, which appears to be a key player in this natural immune-suppression system."

The discovery opens intriguing new pathways to understanding and fighting immune disorders. "In some cases of autoimmune disease, maybe this process breaks down," Ma speculated. "For instance, deficiencies in the clean-up of dying cells have been linked to lupus for a long time. And IL-12 is so key to so many of these common immune disorders -- if we could find out how to suppress or induce its expression, maybe we could find new treatments to fight diseases like lupus or rheumatoid arthritis."

The finding, he said, might even lead to treatments against diseases characterized by a severe weakening of the immune system, as happens during infection with HIV.