CONTACT: L. E. OHMAN
283 Medical Laboratories
Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Release: Embargoed until 4 p.m. EST Thursday, July 16, 1998
Researchers identify a protein critical for T cell development and
IOWA CITY, Iowa -- Scientists at the University of Iowa have just added
a piece to the puzzle of immune sytem 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 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
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 UI professor of internal medicine, and physiology