How T cells know an invader when they see one

"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," says Michael Birnbaum. "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." (Credit: Med PhotoBlog)

Scientists are using X-ray technology to get a remarkably detailed look at the binding sites on T cells, the foot soldiers of the human immune system.

What they’ve discovered is that remarkable similarities in the structure of binding sites help T cells recognize and respond to an enormous number of disease-causing invaders.

The findings suggest 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.

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Researchers say the findings may also 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,” says Michael Birnbaum, a graduate student at Stanford University. “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.”

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

For the study, published in the journal Cell, 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 3D 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 says. “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,” Birnbaum says. “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.”

Hit-and-miss studies

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,” says Britt Hedman, professor of photon science and science director at SSRL. “To understand the factors behind T-cell-receptor binding to peptides will have major impact on biomedical developments, including vaccine design and immunotherapy.”

Birnbaum led the research in he laboratory of K. Christopher Garcia, the study’s senior author and a professor of molecular and cellular physiology and of structural biology. Additional contributors include Mark Davis at Stanford and Kai Wucherpfennig at the Dana Farber Cancer Institute and Harvard University. National Institutes of Health and the Howard Hughes Medical Institute supported the research.

Source: Stanford University