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Three-Dimensional Structure of the T-Cell Receptor Determined by Scientists at The Scripps Research Institute and R.W. Johnson Pharmaceutical Research Institute

La Jolla, CA. October 11, 1996 - For the first time, scientists at The Scripps Research Institute (TSRI), in collaboration with researchers at R.W. Johnson Pharmaceutical Research Institute, (La Jolla, Calif.), have determined the three-dimensional structure of the T-cell receptor (TCR), a key component of the immune response. Further, they also have determined its orientation bound to a major histocompatibility complex (MHC) molecule, one of the products of a large gene cluster that encodes various proteins of the immune system. These MHC molecules in turn bind to foreign peptides for presentation to the T-cells. Understanding the structure of the TCR and its function may enable scientists to enhance the effectiveness of the immune system through the development of new, highly targeted therapeutics.

According to TSRI President Richard Lerner, M.D., "This is one of the most important structures to be elucidated in the past decade."

The work, "Structure of an [alpha] [beta] T-cell Receptor at 2.5 Å and its Orientation in the TCR-MHC Complex," was published as the cover story of today's issue of Science, by K.Christopher Garcia, Massimo Degano, Robyn L. Stanfield, Anders Brunmark, Michael R. Jackson, Per A. Peterson, Luc Teyton, and Ian A. Wilson. The researchers used a method known as x-ray crystallography to determine the structure.

The function of the immune system is to protect the body from foreign pathogens that can harm it. The central event in the immune response to invading microorganisms is the recognition of foreign peptides bound to major histocompatibility complex molecules by the T-cell receptor. Once this occurs the body can mount an immune response to counteract and destroy the invading pathogens.

Scientists have speculated that the key to therapeutic control over immune responses may lie in improved understanding of the formation and operation of different sets of T-cells. One property of T-cells, the "helper function," is to assist B cells to make antibodies to specific antigens. A second property is to kill cells that have been rendered antigenically foreign by viral infection or malignant transformation, the so-called cytotoxic or "killer" function. A third, or suppressor function, controls the mechanism that keeps the immune system finely tuned. An indirect effect of these T-cell functions is the rejection of grafts as foreign if they are not well matched from donor to recipient.

Ian A. Wilson, D.Phil., Member, TSRI Department of Molecular Biology, explains, "Understanding the structural basis for the recognition of foreign peptides in the context of the MHC molecule may lead us to improve antigen recognition and thereby increase the effectiveness of the body's natural defenses. This deeper understanding may provide opportunities to explore new therapeutics that interact with specific regions of these immune system receptors."

In particular, scientists believe that increased knowledge of the structure and function of T-cells may be particularly useful in organ transplantation, in which immunosuppression is essential for the maintenance of transplants; and in cancer, in which treatments direct the patient's immune system against his own tumor cells by forcing the regulatory inducer-suppressor network into a situation favorable to tumor destruction.

The work was funded by grants from R.W. Johnson Pharmaceutical Research Institute, a subsidiary of Johnson & Johnson, The Skaggs Institute for Research, and the National Institutes of Health (which contributed approximately 35% of the funding.)


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