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By Sean Henahan, Access Excellence

Cambridge, MA (Nov. 14 1996) The long-awaited description of the three-dimensional structure of the complex between the human T-cell receptor and the antigenic peptide as linked to a major histocompatibility complex molecule should provide new understanding of how specific immunity is achieved and regulated.

Image: 3-D structure of T-cell receptor

The structural interaction between the human T-cell receptor (TCR), and the antigenic peptide as linked to a major histocompatibility complex (MHC) molecule are fundamental to the workings of the immune system. Previous work has shown that when a virus or bacteria invades the body, the immune system first breaks up cells infected by the invaders. These infected cells are 'flagged" with a combination of the foreign protein and an MHC molecule and bound to a TCR. Roving T-cells then recognize and destroy these flagged cells.

But until now, no one has known what the atomic structure of this immune interaction looked like. Harvard researchers, led by Don C. Wiley of the Department of Molecular and Cellular Biology, determined that TCR structure resembles that of another key component of the immune system, antibodies, particularly, the anitgen-binding region. This discovery led the way to the identification of the entire structure of the MHC-TCR complex.

The research indicates that the antigenic peptide produced by degradation of the invading virus within the cell is held within the MHC binding cleft almost like a hot-dog is held in a bun. This peptide and most of the MHC molecule are engulfed by the TCR.

In a related study, researchers at the University of Maryland Biotechnology Institute gained new insight into the phenomenon of superantigen creation. In some cases, the TCR-MHC interaction leads to an overreaction by T-cells. This overactive immune creates superantigens have that have been implicated in diseases and complications as varied as toxic shock syndrome, diabetes mellitus and multiple sclerosis.

The researchers showed for the first time how a superantigen protein (in this case, the peptide toxin produced by the bacterium Staphylococcus aureus) binds to the TCR. The work showed that by bringing the MHC and TCR together directly, regardless of the peptide bound to the MHC, the superantigen circumvents the normal mechanism for T-cell activation by specific peptide-MHC complexes, and triggers a more general reaction instead.

The basis for the current work can be traced back to 1974, when Drs. Rolf Zinkernagel and Peter Doherty determined that killer T-cells sense infected target cells by the identification of viral antigens displayed on the cell surface in combination with MHC proteins. This process has become known as MHC restriction. The two scientists shared the Nobel prize this year for this work.

Both studies mentioned in this article, along with a commentary appeared in Nature, VOL.384, 14 November 1996. Related research was published in Science, October 11, 1996 (Garcia et al.)

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