The vertebrate immune system is a powerful weapon against external pathogens and cancer cells. T cells play a curative role in this context. They carry a special receptor called a T-cell receptor on their surface that recognizes antigens (small protein fragments from bacteria, viruses, and infected or cancerous body cells) that are presented by specialized immune complexes. Therefore, the T-cell receptor is largely responsible for distinguishing between “self” and “foreign”. Upon binding of an appropriate antigen to the receptor, a signaling pathway within the T cell is activated that “arms” the cell for the respective task. However, how this signaling pathway is activated has remained a mystery until now, despite the fact that the T cell receptor is one of the most studied receptor protein complexes.
Many surface receptors transmit signals inside the cell by changing their spatial structure after ligand binding. Until now it was assumed that this mechanism also belonged to the T-cell receptor. The researchers led by Lukas Sušac, Christoph Thomas and Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt, 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. by visualizing the structure of a membrane-bound T-cell receptor complex with bound antigen. A comparison of the antigen-bound structure captured by cryo-electron microscopy with that of an antigen-free receptor provides the first clues to the mechanism of activation.
For the structural analysis, the researchers chose a T-cell receptor used in immunotherapy to treat melanoma and which had been optimized for this purpose in several steps so that it binds as strongly as possible to its antigen A particular challenge in the way to determine the structure was to isolate the entire assembly of the antigen receptor consisting of eleven different subunits from the cell membrane. “Until recently, no one believed it would be possible to extract such a large membrane protein complex in a stable form from the membrane,” says Tampé.
Once they had successfully achieved this, the researchers used a trick to remove those receptors from the preparation that had survived the process and were still functional: because of the strong interaction between the receptor complex and the antigen, they were able to “fish “. one of the most medically important immune receptor complexes. Subsequent images collected in the cryo-electron microscope provided groundbreaking insight into how the T-cell receptor works, as Tampé summarizes: “From our structural analysis, we were able to show how the T-cell receptor it assembles and recognizes antigens. and hypothesize how signal transduction is triggered after antigen binding.” According to their results, the big surprise is that there is evidently no significant change in the spatial structure of the receptor after antigen binding, since it was practically the same both with and without antigen.
The remaining question is how antigen binding could lead to T cell activation. The CD8 co-receptor is known to approach the T cell receptor after antigen binding and stimulates the transfer of phosphate groups to its intracellular part. The researchers assume that this leads to the formation of structures that exclude enzymes that cleave phosphate groups (phosphatases). 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 is an important stimulus to employ the T-cell receptor in a therapeutic context to treat infections, cancer and autoimmune diseases.”
Publication: Lukas Sušac, Mai T. Vuong, Christoph Thomas, Sören von Bülow, Caitlin O’Brien-Ball, Ana Mafalda Santos, Ricardo A. Fernandes, Gerhard Hummer, Robert Tampé, Simon J. Davis: Structure of a Fully Assembled Tumor -specific T-cell receptor bound by pMHC. Cell (2022) 185, 18 August https://doi.org/10.1016/j.cell.2022.07.010
Image download: https://www.uni-frankfurt.de/123390758
Caption: Cryo-EM structure of the fully assembled T-cell receptor (TCR) complex with a tumor-associated peptide/MHC ligand provides important insights into the biology of TCR signaling. These insights into the nature of TCR assembly and the unusual cell membrane architecture reveal the basis of antigen recognition and receptor signaling.
More information:
Professor Robert Tampé
Collaborative Research Center CRC 1507 – Protein assemblies and machinery in cell membranes
Institute of Biochemistry, Biocentre
Goethe University Frankfurt
Tel.: +49 69 798-29475
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