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Atomic structure of a T cell receptor binding to a peptide-MHC complex (1996)

TCR binding peptide MHC

Seeing is believing. This is a truism in immunology just as it is in many spheres of science. The story of the first X-ray crystallography image of T-cells binding to the antigens “presented” by the major histocompatibility complex are a good example of being able to believe that something is right because you can see it.

Scientists had worked out how T-cells mounted an immune response against pathogen-infected cells in the 1970s. They realised that when a virus or bacterium infects a cell, partially digested bits of the pathogen’s macromolecules, called peptides, are displayed or “presented” on the cell’s surface by a complex collection of protein molecules encoded in the major histocompatibility complex (MHC). It is a way of flagging to the immune system that pirates had boarded the ship. The signal alerts the T-cells – so-called because they are made in the thymus – to recognise the peptides as “foreign” and so mount an immune response by binding to the peptide-MHC complex, so leading to the killing of these infected target cells. Peter Doherty and Rolf Zinkernagel, working at the John Curtin School of Medical Research in Canberra, Australia, were the first to demonstrate this in studied published in 1974, which earned them a share of the Nobel Prize in Physiology or Medicine.

But seeing is believing. In 1996, the same year that Zinkernagel and Doherty received their Nobel, Harvard University’s Don Wiley used X-ray crystallography to capture the first high-resolution images of all three players involved in T-cell activation. The images showed how the T-cell receptor – a specialised set of proteins involved in T-cell activation – binds to the MHC-peptide structure. The imaging feat was described as the holy grail of immunology because it finally showed how this critical part of the cellular immune response worked at the 3-D molecular level. Seeing how the T-cell receptors bind to the MHC-antigen complex enabled immunologists to truly grasp the finer details of how a T-cell receptor recognises antigens on the surface of cells, with important implications for developing vaccines, preventing the rejection of tissue transplants and in the understanding of autoimmune disease.

Don Wiley eloquently communicated the implications of his discovery in a series of lectureships entitled “seeing is believing”. He won many prizes for his achievement and would surely have been a contender for a Nobel had he not died tragically in 2001 from falling off a bridge into the Mississippi river. Memphis police concluded that his fall was accidental.