May 11, 1999 CHAMPAIGN, Ill. -- University of Illinois scientists have come up with a way to improve the properties of T-cell receptors -- and potentially other proteins. Their success opens the door to manipulating a virtually untapped portion of the immune system to fight a variety of autoimmune and viral diseases. In a biotechnological breakthrough, the researchers showed that mutations within two regions of the receptor protein allowed it to be displayed on the surface of yeast. The work appears in the May 11 issue of the Proceedings of the National Academy of Sciences.
The researchers used a yeast-display system, which was created earlier at the U. of I., in combination with directed evolution -- a genetic engineering process in which a protein is subjected to random amino-acid changes, and then only those proteins with desired properties are selected. Their selection process also involved the use of flow-cytometry equipment at the U. of I. Biotechnology Center.
"T-cells and their T-cell receptors represent one-half of the immune system's capability to recognize infection," said David M. Kranz, a professor of biochemistry. "There has not been a method available to engineer these like you can do with antibodies. This paper shows that we've found a way to begin engineering the recognition molecules from the T-cell immune system. Realistically, we're a long way from seeing new therapeutic approaches, but the development of this capability is a major initial step."
Such a strategy could prove beneficial in manipulating the immune system's ability to bind to infected cells, such as in the case of the AIDS virus or cancer where the infection often remains invisible to antibody-based treatments.
Likewise, the researchers said, genetically engineered receptors could be used to block inappropriate immune responses in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
Scientists around the world have been refining a variety of monoclonal antibodies -- proteins similar to those that occur naturally in the immune system that search for and bind to specific antigens -- since the 1970s. However, similar refinements to T-cell receptors have not been possible for reasons that were unclear.
The structure of antibodies and T-cell receptors are remarkably similar, the researchers said, but the responses of each are carried out very differently.
"The immune system looks around for things that don't belong," said K. Dane Wittrup, the James W. Westwater professor of chemical engineering at the U. of I. "The two major classes of molecules that accomplish this are the recognition proteins -- antibodies and T-cell receptors. We are working at the contact point of where the immune system decides something does or doesn't belong."
Their findings offer the hope of doing genetic engineering directly on recognition molecules from the T-cell system, a therapeutic approach that has never been done. "In addition, this strategy for T-cell receptors may be of general use in the study and directed evolution of other proteins that to date have been impossible to improve," Kranz said.
The yeast-display system used in the experiments was created in Wittrup's lab and published in 1997. The system allows for a library of mutant proteins to be screened for proteins with improved binding properties or other features. These improvements can have considerable practical uses in medicine, agriculture or other industries.
The National Institutes of Health and the Whitaker Biomedical Engineering Foundation provided funding for the research. In addition to Kranz and Wittrup, authors of the PNAS paper were U. of I. graduate students Michele C. Kieke, Eric V. Shusta and Eric Boder, and Luc Teyton of the Scripps Research Institute.
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