July 20, 1998 IOWA CITY, Iowa -- Scientists at the University of Iowa have just added a piece to the puzzle of immunesytem activation. Stimulation of the immune system involves more than a binary on-off response. When a foreign body attaches to a T cell receptor, it sets off a chain of biochemical reactions that lead to immune system activation.
Gary Koretzky, M.D. Ph.D., UI Kelting Professor of Rheumatology, reports that the protein SLP-76 appears to be critical for the development and activation of T cells, an important part of the immune system. This finding is reported in the July 17 issue of Science magazine.
The finding provides scientists with a better understanding of the basic biology of immune system activation, which is critical to understanding immunodeficiency disorders and autoimmune diseases, such as rheumatoid arthritis, diabetes and systemic lupus.
Activation of the specialized receptor for foreign substances, the T cell antigen receptor, starts a cascade of biochemical events that lead to T cell activation. This cascade involves the activation of proteins which then activate other proteins in succession until the T cell itself is stimulated. The proteins in this series, or pathway, are referred to as second messengers. Koretzky's interest in learning more about this second messenger signaling pathway and how the proteins communicate with each other led to identification of the protein SLP-76in 1995.
"What is striking about this molecule is that it isn't a an enzyme like most of the other molecules in the signaling pathway. It is an adapter protein," Koretzky said. Adapter proteins bind proteins together. They don't catalyze reactions like enzymes, but they can enhance reactions by creating a bridge that brings proteins together.
"Our thinking was that perhaps SLP-76 played an important role in lymphocyte (white blood cell) activation," Koretzky said. He and his colleagues tested this hypothesis by manipulating the gene that produces the SLP-76 protein in cultured cells. The results supported their theory.
There are benefits to doing experiments in cell lines in culture but there are also limitations, so Koretzky did more experiments in mice in which the gene that codes for SLP-76 was eliminated, or "knocked out". The knockout mouse was developed by James Clements, Ph. D., in Koretzky's laboratory along with a team led by Roger Williamson, M.D., UI professor of obstetrics and gynecology.
"The most striking feature of the mouse is that there is a block in T cell development leaving the mice completely deficient in this cell type," Koretzky said. "The conclusion is that SLP-76 is absolutely critical for at lease one essential feature of the immune system -- the development and activation of T cells."
SLP-76 appears to be as important as any of the other molecules in the signaling pathway that stimulates the immune system, Koretzky said. That is the major finding reported in Friday's issue of Science.
These findings suggest that SLP-76 may play a role in the development of disease. Though T cells comprise only one part of the immune system, they play a critical role in immune system function. People lacking T cells are extremely susceptible to infection and will die without a transplant. There are a number of people who are immunodeficient, Koretzky said, and physicians understand the cause in only about half the cases. Koretzky is interested in collaborating with other scientists to learn if a lack of SLP-76 is involved in some cases of immunodeficiency disorder with an unknown cause.
In addition to investigating the role of SLP-76 in immunodeficient people, Koretzky and his colleagues are putting the molecule back into the SLP-76 deficient mice in both a normal and mutated form to better understand how the molecule works. If replacing the protein in the SLP-76-decifient mouse increases the number of functioning T cells, this may led to possible future therapies, but Koretzky said, at this point it is only a glimmer of hope at the end of a long road.
Dr. Koretzky is a University of Iowa professor of internal medicine, and physiology and biophysics.
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