Mayo Researchers Discover Key Step in Immune System Development

Tuesday, August 23, 2005

ROCHESTER, Minn. — Mayo Clinic researchers have discovered a key step in the early development of the immune system by showing that a specific protein is essential for the creation of T cells. T cells are the basic, but aggressive infantry of white blood cells that defend against invading organisms. Researchers report their findings on the protein called CAML (calcium modulating cyclophilin ligand) in today's early online edition of Immunity (opens in new window).

"T cells really are the masterminds that control the immune response and production of antibodies, and play an important role in tumor surveillance — so we want to know where they come from and how they function," says Mayo Clinic pediatric oncologist and lead researcher Richard Bram, M.D., Ph.D. "This finding could also help us with immune deficiency or autoimmunity diseases we see in pediatrics." Because T cells are involved in certain cancers, understanding the pivotal role of CAML in T cell development may lead to new strategies for interrupting the disease process in cancers characterized by T cell overproduction, such as leukemia and lymphoma. Diseases characterized by T cell underproduction also may be targets for therapies based on this research.

Background Biology: Thymus as T Cell School

As potential T cells develop in a child's thymus, a stringent quality control process occurs in which three things can happen to potential T cells. In effect, these potential T cells are in school in the thymus. The three things that can happen to them are:

• Most flunk T cell school. They don't "learn" to react to invaders. They cannot help police the immune system and naturally die.
• Some "learn" the wrong lesson. They recognize the person's own tissues and misconstrue them to be foreign. This is a potentially lethal reaction — an attack against self called an autoimmune attack. In a healthy body, these misguided cells are destroyed in the thymus so they can't get out into the body to start an autoimmune reaction.
• Some become "model students." They master the tricky balance between learning to identify foreign invaders and attacking them, and to tolerate a person's own cells and not attacking them. These cells "graduate" into the immune system as able members and are released into the body.

To understand how a functional balance is supported so a strong immune response is maintained — but not so strong that it provokes autoimmunity — the Mayo group turned to CAML. "The role of the protein wasn't known," Dr. Bram explains, "but we suspected it might be involved in maintaining this critical balance." To test the hypothesis, the researchers bred a line of laboratory mice that lacked the CAML gene. The researchers concluded that CAML is essential for thymocyte (T cells guarding the thymus gland) development because thymocytes of these mice lacking CAML had higher rates of programmed cell death.

While the mechanism by which CAML works is not fully known, Dr. Bram says the Mayo Clinic researchers discovered another aspect of it. They are the first to report that CAML works biochemically to alter the signal strength that cues specific commands to the developing thymocytes. Without CAML to partner with as a key modulator, the process goes awry and the "student thymocytes" die.

Collaboration and Support

In addition to Dr. Bram, the Mayo Clinic research team includes: David Tran; Contessa Edgar; Karin Heckman; Shari Sutor; Catherine Huntoon; Jan van Deursen, Ph.D. and David McKean, Ph.D. Their work was supported by the National Institutes of Health.

###

To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories.

###

To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. MayoClinic.com is available as a resource for your health stories.