Researchers decipher chemical “cross talk” that determines survival of immune cells

Molecular biologists at the University of California, San Francisco have deciphered a pattern of signals that spells life or death to each T cell of the immune system and may control the development of the body’s natural defense arsenal.

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 post- doctoral scientist working in the lab of senior author Keith Yamamoto.

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 interaction is complex. A strong signal from either the glucocorticoid receptor or the T cell receptor –in the absence of the other –kills immature and some mature T cells. But together, the two signals rescue T cells from death, or apoptosis.

What Jamieson and Yamamoto discovered in experiments with mouse cells is the nature of the T -cell receptor signal that interacts with an otherwise deadly GR signal. This chemical pathway, known as Ras-MEK, was already known to be crucial to “positive selection,” the process that determines which immature T cells will survive the harsh winnowing process -“which members of the T cell chorus will be able to stay and play,” as Yamamoto puts it. The process of positive selection has remained elusive to biologists.

The UCSF scientists suggest that the interplay between the hormone signal and the T cell receptor signal may select for T cells with different levels of activity in the immune response. The varying hormone levels washing over different populations of immature T cells subject them to a broad range of physiological conditions the body will face. Different T cells succumb to different levels of GR and TCR signals, but those that survive –those that have been selected through this process –are well suited for the job of protecting the organism through a lifetime of various insults without attacking the body in the process -the hallmark of autoimmune disorders.

In key experiments using spleen cells from mice Jamieson and Yamamoto showed that a well-studied gene called Ras triggers the pathway that rescues T cells from GR death signals.

“Ras acts as a molecular switch at the nexus of several incoming signals and, in turn, activates a network of multiple pathways,” Jamieson explains.

Using cells with mutant Ras genes as probes, Jamieson and Yamamoto determined the specific Ras-initiated pathway that rescues the immature T cells. It involves the gene MEKl, and they showed this pathway is necessary and sufficient to prevent GR-induced apoptosis.

In their effort to unravel the snarl of signals that ultimately turns genes on or off, Jamieson and Yamamoto showed that a chemical pathway triggered by the immune system interacts with one from a hormone receptor to control the fate of T cells. This interplay may well determine which kinds of T cells survive, and the process of selection defines the very nature and effectiveness of the arsenal we depend on for life.

Jamieson and Yamamoto also wanted to find out if the TCR-triggered rescue of T cells from GR-induced death involves a change in the way GR regulates genes that code for T cell death. Since the genes involved in GR-induced apoptosis are not known, they turned to “surrogate” reporter genes already known to be controlled by the glucocorticoid receptor (GR). They found that the Ras-MEK signaling pathway that inhibits glucocorticoid-induced apoptosis did indeed alter the activity of GR. They concluded that the crosstalk signaling from the TCR clearly affects the ability of GR to regulate genes.

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.

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