Goethe University: First atom-level image of T-cell receptor with bound antigen

T cells are tailor-made tools of our immune system in the fight against infectious diseases and cancer cells. On their surface, these white blood cells carry a receptor for recognizing antigens. With the help of cryo-electron microscopy, biochemists and structural biologists from the Goethe University Frankfurt, in cooperation with the University of Oxford and the Max Planck Institute for Biophysics, were able to elucidate the complete T cell receptor complex with bound antigen at atomic resolution for the first time. In this way, they were able to improve the understanding of a fundamental process and lay the foundation for future treatment options for serious diseases.

The immune system of vertebrates is a powerful weapon against pathogens from outside and degenerated cells of their own body. The T-cells play a special role in this. These carry a receptor on their surface for recognizing antigens – small protein fragments from bacteria, viruses and infected or degenerated body cells – which are presented to them by specialized immune complexes. The T-cell receptor is thus essentially responsible for distinguishing between “self” and “foreign”. After a suitable antigen has bound to the receptor, a signaling pathway is switched on inside the T cell, which “arms” the T cell for its respective task. So far, however, it has remained a mystery how this signaling pathway is activated – and that

Many surface receptors transmit signals into the interior of cells by changing their spatial structure after binding their ligand. So far, this mechanism has also been suspected for the T-cell receptor. Scientists led by Lukas Sušac, Christoph Thomas and Robert Tampé from the Institute of Biochemistry at Goethe University, in collaboration with Simon Davis from the University of Oxford and Gerhard Hummer from the Max Planck Institute for Biophysics, have now succeeded for the first time in determining the structure of a Visualize membrane bound T cell receptor complex with bound antigen. A comparison of the structure obtained via cryo-electron microscopy with that of a receptor without bound antigen provides first indications of the activation mechanism.

For the structural analysis, the researchers selected a receptor that is used in immunotherapy to treat melanoma and had been optimized in several steps so that it binds its antigen as readily as possible. A particular challenge was to isolate the entire antigen-receptor complex, consisting of eleven different subunits, from the cell membrane. “Until recently, nobody would have thought that it was even possible to stably release such a large membrane-protein complex from the membrane,” says Tampé.

Once they had succeeded, the researchers used a trick to fish out the receptors from the experimental approach that had survived the dissolving process and were still functioning: Due to the strong and selective interaction between receptor complex and antigen, they were able to “fish” for one of the most medically relevant immune receptor complexes. . The subsequent images with the cryo-electron microscope provided groundbreaking insights into how the T-cell receptor works, as Tampé summarizes: “Based on our structural analysis, we were able to show how the T-cell receptor recognizes antigens and formulate hypotheses about how the signal is transmitted to antigen binding is set in motion.” So the big surprise is that

The question that remains is how antigen binding could lead to T cell activation instead. It is known that after antigen binding, the CD8 co-receptor attaches itself to the T-cell receptor and stimulates the transfer of phosphate groups to its intracellular part. The researchers suspect that this leads to the formation of structures to which enzymes that split off phosphate groups (phosphatases) no longer have access. If these phosphatases are missing, the phosphate groups remain stable on the T cell receptor and can trigger the next step in the signaling cascade. “Our structure is a blueprint for future studies on T cell activation,” Tampé is convinced. “In addition, it provides important impetus to make the T cell receptor therapeutically usable for the treatment of infections, cancer and autoimmune diseases.”