(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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Science