September 21,
2001
Immune Cells SLAP Internal Signals
Together
SLAP Protein Signal Found to Connect Components of
Immune Cell Activation: Finding Has Implications for Cancer
Treatments and Autoimmune Diseases
(Philadelphia,
PA) - In a way, the immune system works like throwing
a fistful of darts while blindfolded - if you throw
enough some may actually hit the dartboard. Since the
immune system does not know ahead of time what a particular
threat looks like, it generates T cells, a type of white
blood cell, with uniquely random T cell receptors (TCRs).
Once the TCR gets activated - by latching onto a target
- it begins a cascade of signals and counter-signals
that work in order to prepare the T cell for action.
In this week's issue of the journal, Science, researchers
from the University of Pennsylvania School of Medicine
report their findings on the role of one signal, the
SLAP-130 protein, in bridging together chemical pathways
in order to activate T cells.
"Once the immune system finds the TCR that sticks
to a specific target, it generates more copies of that
T cell and readies them to seek out the target - a process
that is regulated by an intricate network of chemical
reactions," said Gary A. Koretzky, PhD, professor
in the Penn Department of Pathology and Laboratory Medicine,
and researcher for the Abramson Family Cancer Research
Institute at the Penn Cancer Center. "Part of our
goal is to figure out which signal does what in this
activation process."
According to Koretzky, the SLAP-130 protein is an integral
part of generating an immune response. Using a mouse
model, Koretzky and his colleages were able to place
SLAP-130 in the chain of reactions that couple TCR activation
with the activation of integrins, large molecules on
the outside of T cells that help them stick to their
targets. Without SLAP-130 to link the two processes
together, T cells are not able to get the integrins
to work properly.
"By identifying how T cells are activated, we hope
to gain a better understanding of how T cells function
properly in the control malignant of growths and how
they do not function properly in autoimmune disorders,"
said Koretzky. "That is, we would like to know
more about how to turn T Cells on when we need them
and turn them off when we don't."
Part of learning how to control T cells is learning
how the signaling process works within T cells. To do
so, Koretzky and his colleagues have been looking at
the network of reactions step by step. SLAP-130 was
discovered in association with another T cell protein
named SLP-76. SLP-76 forms scaffolding, a physical structure
within the cell where chemical reactions can take place.
Like SLP-76, the SLAP-130 protein works as an adapter
molecule, which recruits other molecules to various
parts of the cell.
In this case, SLAP-130 has a role in adapting the integrin
molecules in clusters outside of the cell. Those integrin
clusters serve to secure the immune cell to its target,
which can then be destroyed to eliminate the threat.
Although mice lacking SLAP-130 could generate mature
T cells, they could not form working clusters of integrin
molecules once the cell was activated and, therefore,
they do not bind as well to their target.
The researchers believe that this information will be
useful in combating diseases such as cancer, where it
would be useful to be able to turn on T cells to target
malignant tumors. They also theorize that such knowledge
would be useful in treating autoimmune disorders, where
it would be useful to turn off T cells in order to prevent
them from attacking healthy cells.
"In order to figure out how to fix something, you
first need to figure out how it works," explained
Koretzky.
Contributors to this research include researchers from
the Abramson Family Cancer Research Institute at Penn,
the Penn School of Veterinary Medicine, and the University
of Minnesota Medical School.
Their research has been funded by the National Institutes
of Health and The Leonard and Madlyn Abramson Family
Cancer Research Institute at the University of Pennsylvania
Cancer Center.
# # #
The University of Pennsylvania Health System is distinguished
not only by its historical significance - first hospital
(1751), first medical school (1765), first university
teaching hospital (1874), first fully integrated academic
health system (1993) - but by its position as a major
player on the world stage of medicine in the 21st century.
Penn ranks second among all American medical schools
that receive funds from the National Institutes of Health,
perhaps the single most important barometer of research
strength.
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