Deciphering Chemical "Cross Talk" That Determines Immune Cell Survival

When a virus, parasite or other pathogen invades a cell, the immune system’s T cells recognize the enemy, and a potent chemical signal is triggered using a docking site known as the T-cell receptor. The current research identifies a possible new role for this chemical message. The scientists suggest that the interplay between this signal and one produced by a hormone continually selects the T-cell soldiers the body needs as it faces a changing cast of invaders. What controls this selection process has long puzzled biologists.

The steroid hormone signal is normally present at low levels that fluctuate with daily rhythms, but stress can cause the hormone levels to spike. The new study may lead to a molecular understanding of how stress-induced hormone imbalance depresses immune system function, the scientists say. This imbalance sometimes leads the immune system to activate T cells that attack the body and cause autoimmune diseases.

The research was carried out to help clarify a larger question: how the cacophony of chemical messages streaming through a cell is ultimately "heard" as a single command to switch a gene on or off -- the fundamental unit of action in the cell.

"Signals from the environment, from hormones and many other sources are woven into a fabric," explains UCSF’s Keith Yamamoto, PhD, professor and chair of molecular and cellular pharmacology. "It is the fabric that defines the state of the cell at any given time and determines whether or not genes are activated. We wanted to examine how different signals become integrated to produce instructions to the genetic machinery."

The scientists’ findings are published in the June 20 issue of the Proceedings of the National Academy of Sciences. Lead author is Christina A. M. Jamieson, PhD, a UCSF postdoctoral scientist working in Yamamoto’s lab.

Yamamoto is an expert on glucocorticoid receptors, proteins that bind the glucocorticoid hormone and directly regulate genes involved in a large number of vital functions such as the control of blood pressure, blood sugar levels, and control of T-cell fate. Because signals from the glucocorticoid receptor (GR) are known to affect T-cell development, Yamamoto and Jamieson recognized that studying the "crosstalk" between messages from GR and T-cell docking sites could provide a window on the way signals interact to direct gene activity.

The findings in mice cell cultures are expected to apply to humans since glucocorticoids regulate genes in much the same way in humans and are used to treat many human autoimmune diseases.

Strong drugs that are derivatives of corticosteroid hormones are among the most effective treatments for autoimmune diseases such as rheumatoid arthritis, the researchers point out, although how the hormone exerts its effects on the immune system has been unclear. Understanding how the hormone works in the immune system may allow better targeting of hormone therapy to minimize serious side effects of its use, such as osteoporosis.

The research may also provide a new tool against cancer, the scientists report. Hormone therapy to combat breast and prostate cancers is often compromised when cancer cells grow resistant to the hormone effect. The new research identifies a signal from the T-cell receptor that cancels out such hormone messages. A drug that inhibits this signal, they suggest, could re-sensitize cancer cells to hormone therapy.