T cells are our immune system’s customised tools for fighting infectious
diseases and tumour cells. On their surface, these special white blood cells
carry a receptor that recognises antigens. With the help of cryo-electron
microscopy, biochemists and structural biologists from Goethe University
Frankfurt, in collaboration the University of Oxford and the Max Planck
Institute of Biophysics, were able to visualise the whole T-cell receptor
complex with bound antigen at atomic resolution for the first time. Thereby
they helped to understand a fundamental process which may pave the way for
novel therapeutic approaches targeting severe diseases.
The immune system of vertebrates is a powerful weapon against external
pathogens and cancerous cells. T cells play a curcial role in this context.
They carry a special receptor called the T-cell receptor on their surface that
recognises antigens – small protein fragments of bacteria, viruses and
infected or cancerous body cells – which are presented by specialised immune
complexes. The T-cell receptor is thus largely responsible for distinguishing
between “self” and “foreign”. After binding of a suitable antigen to the
receptor, a signalling pathway is triggered inside the T cell that “arms” the
cell for the respective task. However, how this signalling pathway is
activated has remained a mystery until now – despite the fact that the T-cell
receptor is one of the most extensively studied receptor protein complexes.
Many surface receptors relay signals into the interior of the cell by changing
their spatial structure after ligand binding. This mechanism was so far
assumed to also pertain to the T-cell receptor. 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 of
Biophysics, have now succeeded for the first time in visualizing the structure
of a membrane-bound T-cell receptor complex with bound antigen. A comparison
of the antigen-bound structure captured using cryo-electron microscopy with
that of a receptor without antigen provides the first clues to the activation
mechanism.
For the structural analysis, the researchers chose a T-cell receptor used in
immunotherapy to treat melanoma and which had been optimised for this purpose
in several steps in such a way that it binds its antigen as tightly as
possible. A particular challenge on the way to structure determination was to
isolate the whole antigen receptor assembly consisting of eleven different
subunits from the cell membrane. “Until recently, nobody believed that it
would be possible at all to extract such a large membrane protein complex in a
stable form from the membrane,” says Tampé.
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| The 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. |
Once they had successfully achieved this, the researchers used a trick to
fish those receptors out of the preparation that had survived the process
and were still functional: due to the strong interaction between the
receptor complex and the antigen, they were able to “fish” one of the most
medically important immune receptor complexes. The subsequent images
collected at the cryo-electron microscope delivered groundbreaking insights
into how the T-cell receptor works, as Tampé summarises: “On the basis of
our structural analysis, we were able to show how the T-cell receptor
assembles and recognises antigens and hypothesise 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 receptor’s
spatial structure after antigen binding, as this was practically the same
both with and without an antigen.
The remaining question is how antigen binding could instead lead to T-cell
activation. The co-receptor CD8 is known to approach the T-cell receptor
after antigen binding and to stimulate the transfer of phosphate groups to
its intracellular part. The researchers assume that this leads to the
formation of structures which exclude enzymes that cleave off phosphate
groups (phosphatases). If these phosphatases are missing, the phosphate
groups remain stable at the T-cell receptor and can trigger the next step of
the signalling cascade. “Our structure is a blueprint for future studies on
T-cell activation,” Tampé is convinced. “In addition, it’s an important
stimulus for employing the T-cell receptor in a therapeutic context for
treating infections, cancer, and autoimmune diseases.”
Reference:
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 ligated by pMHC. Cell (2022) 185, Aug 18
DOI: 10.1016/j.cell.2022.07.010
Tags:
Medical Science