Researchers discover immune system's rules of engagement

by Glenn Roberts Jr.
Stanford School of Medicine researchers, working with scientists at the SLAC National Accelerator Laboratory, have made discoveries about the ways in which T cell receptors (shown in bright red) recognize invaders in the body. Credit: Eric Smith & K. Christopher Garcia

(Medical Xpress)—A study led by researchers at Stanford's School of Medicine reveals how T cells, the immune system's foot soldiers, respond to an enormous number of potential health threats.

X-ray studies at the Department of Energy's SLAC National Accelerator Laboratory, combined with Stanford biological studies and , 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.

The research demonstrates a faster, more reliable way to identify large numbers of antigens, the targets of the immune response, which could speed the discovery of disease treatments. 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, called peptides, 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 approach

In 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 science

Finding 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. "To understand the factors behind T-cell-receptor binding to will have major impact on biomedical developments, including vaccine design and immunotherapy."

More information: "Deconstructing the Peptide-MHC Specificity of T Cell Recognition," Michael E. Birnbaum, Juan L. Mendoza, Dhruv K. Sethi, Shen Dong, Jacob Glanville, Jessica Dobbins, Engin Özkan, Mark M. Davis, Kai W. Wucherpfennig, K. Christopher Garcia. Cell, Volume 157, Issue 5, p1073–1087, 22 May 2014
DOI: dx.doi.org/10.1016/j.cell.2014.03.047

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betterexists
not rated yet May 23, 2014
From time to time, there have been similar cases of availability of Fodder to Pounce upon like a Swarm of Flies for the Scientists....But, the Bottleneck is the Availability of Funds to Move to that Fodder
Society Squanders that Away on gAd leaving little for useful purposes such as this. Detailed Statistics on this Angle of Human Activity should provide the Extent of Drainage!
Realistic Scientists should Proactively wage a war on gAd as their bitterest Enemy... as one good for Nothing!
betterexists
not rated yet May 23, 2014
From time to time, there have been similar cases of availability of Fodder to Pounce upon like a Swarm of Flies for the Scientists....But, the Bottleneck is the Availability of Funds to Move to that Fodder
Society Squanders that Away on gAd leaving little for useful purposes such as this. Detailed Statistics on this Angle of Human Activity should provide the Extent of Drainage!
Realistic Scientists should Proactively wage a war on gAd as their bitterest Enemy... as one good for Nothing!

For Example, Scientists recently found a rare group of people who are naturally immune to malaria; Blood from a rare group of children from Tanzania, found to be naturally immune to malaria should help scientists to take a giant leap in developing a vaccine against the world's deadliest vector borne disease.
Read "Immune children aid malaria vaccine hunt" on BBC News
betterexists
not rated yet May 23, 2014
This should spur studies further into DNA changes in T-Cells that are directly related to their receptors on their cell surfaces!
The Speciality of Geneticists is that they can tinker even the Biggest Multicellular beings by attacking them at their most vulnerable Unicellular Level....The Shortest shortcut possible in Biotechnology!
Again, Everything that may possibly be discovered is directly related to the easy availability of funds for research.
Also, Until Plants can be digested easily to make the ESSENTIAL biofuels... It is high time to make attempts to resurrect mediocre-sized herbivores, if not Giant Dinosaurs. Work in Genetics must grow ASAP by thousand-folds or even by million-folds.
Based on studies on Ancient DNA extracted from bones of two elephant birds held by the Museum of New Zealand, University of Adelaide Scientists now confirm That The Diminutive Kiwi actually once flew, solving the 150-year-old evolutionary mystery — Kiwi is now found to be more closely related to the extinct Madagascan elephant bird — a 2-3 metre tall, 275 kg giant....not to the hitherto thought to be, the other flightless bird of Australia, Emu.
Why are Animals are getting Dimunitive OR Assuming Mountainous Sizes?
There is NO necessity for Humans to have So Many Blood Groups making it a so tough for the Injured to Survive in the Hospitals!
betterexists
not rated yet May 23, 2014
This should spur studies further into DNA changes in T-Cells that are directly related to their receptors on their cell surfaces!
The Speciality of Geneticists is that they can tinker even the Biggest Multicellular beings by attacking them at their most vulnerable Unicellular Level....The Shortest shortcut possible in Biotechnology!
Again, Everything that may possibly be discovered is directly related to the easy availability of funds for research.
Also, Until Plants can be digested easily to make the ESSENTIAL biofuels... It is high time to make attempts to resurrect mediocre-sized herbivores, if not Giant Dinosaurs. Work in Genetics must grow ASAP by thousand-folds or even by million-folds.
Based on studies on Ancient DNA extracted from bones of two elephant birds held by the Museum of New Zealand, University of Adelaide Scientists now confirm That The Diminutive Kiwi actually once flew, solving the 150-year-old evolutionary mystery — Kiwi is now found to be more closely related to the extinct Madagascan elephant bird — a 2-3 metre tall, 275 kg giant....not to the hitherto thought to be, the other flightless bird of Australia, Emu.
Why are Animals are getting Dimunitive OR Assuming Mountainous Sizes?
There is NO necessity for Humans to have So Many Blood Groups making it a so tough for the Injured to Survive in the Hospitals!
betterexists
not rated yet May 23, 2014
Elephantine Birds...that is...It did not let me edit the above comment.