X-ray studies at the Department of Energy's SLAC National Accelerator Laboratory, combined with Stanford http://www.selleckchem.com/products/nlg919.html, http://www.selleckchem.com/products/BIRB-796-(Doramapimod).html, http://www.selleckchem.com/products/arq-197.html biological studies and computational analysis, revealed remarkable similarities in the structure of binding sites, which allow a given T cell to recognize many different invaders that provoke an immune response.It also may lead to a better understanding of what T cells recognize when fighting cancers and why they are triggered to attack healthy cells in autoimmune diseases such as diabetes and multiple sclerosis."Until now, it often has been a real mystery which antigens T cells are recognizing; there are whole classes of disease where we don't have this information," said Michael Birnbaum, a graduate student who led the research at the School of Medicine in the laboratory of K. Christopher Garcia, the study's senior author and a professor of molecular and cellular physiology and of structural biology."Now it's far more feasible to take a T cell that is important in a disease or autoimmune disorder and figure out what antigens it will respond to," Birnbaum said.T cells are triggered into action by protein fragments, displayed on a cell's surface. In the case of an infected cell, peptide antigens from a pathogen can trigger a T cell to kill the infected cell. The research provides a sort of rulebook that can be used with high success to track down antigens likely to activate a given T cell, easing a bottleneck that has constrained such studies.Combination approachIn the study, researchers exposed a handful of mouse and human T-cell receptors to hundreds of millions of peptides, and found hundreds of peptides that bound to each type. Then they compiled and compared the detailed sequence -- the order of the chemical building blocks -- of the peptides that bound to each T-cell receptor.From that sample set, which represents just a tiny fraction of all peptides, a detailed computational analysis identified other likely binding matches. Researchers compared the 3-D structures of T cells and their unique receptors bound to different peptides at SLAC's Stanford Synchrotron Research Lightsource (SSRL)."The X-ray work at SSRL was a key breakthrough in the study," Birnbaum said. "Very different peptides aligned almost perfectly with remarkably similar binding sites. It took us a while to figure out this structural similarity was a common feature, not an oddity -- that a vast number of unique peptides could be recognized in the same way."Researchers also checked the sequencing of the peptides that were known to bind with a given T cell and found striking similarities there, too."T-cell receptors are 'cross-reactive,' but in fairly limited ways. Like a multilingual person who can speak Spanish and French but can't understand Japanese, a receptor can engage with a broad set of peptides related to one another," Birnbaum said.Impact on biomedical scienceFinding out whether a given peptide activates a specific T-cell receptor has been a historically piecemeal process with a 20 to 30 percent success rate, involving burdensome hit-and-miss studies of biological samples. "This latest research provides a framework that can improve the success rate to as high as 90 percent," Birnbaum said."This is an important illustration of how SSRL's X-ray-imaging capabilities allow researchers to get detailed structural information on technically very challenging systems," said Britt Hedman, professor of photon science and science director at SSRL.
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