Life and death struggle: Proteins play against each other, bringing balance to immune system

April 27, 2000

Each day, viruses attack the immune system looking to gain a foothold in the body and cause sickness. But the immune system regularly turns away these invaders by using antibodies and killer T cells that attack the antigen. Until now, scientists only knew these that events happened, but not how or why.

A research team at National Jewish Medical and Research Center led by Philippa Marrack, Ph.D., and John Kappler, Ph.D., report in the April 28 issue of Science that they have discovered how certain proteins work together in the immune system to control the T cells that attack viruses such as chicken pox, measles and other diseases.

National Jewish researchers have shown that the proteins IL-15 and IL-2 work together to balance the immune response against antigens. Researchers found that IL-15 drives the production and division of ³memory² killer T cells and IL-2 kills these T cells as they divide.

"Memory" T cells are the immune system's primary defenders against antigens. When the immune system first comes in contact with an antigen‹such as the viruses that cause chicken pox, measles or polio‹it creates killer T cells that then turn into "memory" T cells. If and when the antigen invades the immune system a second time, these "memory" T cells recognize the invader and bind to it, killing the antigen more quickly than during the first exposure. "You get a nuclear holocaust, not just gunfire," said Dr. Marrack, a National Jewish researcher who studies the inner workings of the immune system. (This is why people don't get chicken pox, measles or similar immune diseases more than once.)

Still, researchers were unsure if T cells maintained the ability to remember antigens from one exposure to another‹there could be decades between exposures‹by laying in wait, by being exposed to antigens regularly or by holding on to small parts of the virus. Recently, National Jewish researchers found that none of these explanations were quite right. Rather, "memory" T cells stay alive for many years because they divide slowly, stimulated by a special hormone (cytokine) of the immune system, IL-15. Another immune system cytokine, IL-2, prevents this IL-15-induced production from getting out of control.

Working together, IL-15 and IL-2 help to provide equilibrium to the immune system. When an immune response to an antigen is mounted, IL-15 is produced, which causes T cells to divide and attack the invader and stimulates "memory" T cells. At the same time that IL-15 production increases, IL-2 controls the proliferation of "memory" T cells‹caused by increasing amounts of IL-15‹by killing some T cells as they divide.

"In immune responses," Dr. Marrack said, "the stimulatory effects of one cytokine are frequently counterbalanced by the inhibiting effects of another cytokine. This balance allows the immune system to battle antigens with a controlled response."

Interleukins are a cytokines, proteins, that are secreted by different types of cells in the body, and which regulate the intensity and length of immune responses.

National Jewish scientists believe that this information could help doctors create better treatments in the future for immune diseases such as AIDS, lupus or rheumatoid arthritis. In the future, doctors may be able to use this knowledge to regulate the division of T cells. Changing the balance of the proteins that affect T cells‹in effect regulating the immune response to an antigen‹could be used successfully with medical therapies.

"You might be able to attack that balance by changing either IL-2 or IL-15," Dr. Marrack said.
-end-
Chia Chi Ku, Ph.D., Masaaki Murakami, Ph.D., DVM, and Akemi Sakamoto, M.D., also contributed to this research.

The Number 1 Respiratory Hospital in the U.S. for Two Consecutive Years, U.S. News & World Report, 1998-2000.

www.nationaljewish.org/pa

National Jewish Health

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