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A study from Davis Group is the first to describe the structure of the T-cell receptor when bound to an activating ligand. The findings shed light on an important trigger in the immune system, and suggest a completely new process by which cell receptors can be activated.

© Sušac et al., (2022) Cell
EM density map of the ligand-bound T-Cell Receptor Complex.

In work published in the journal Cell, researchers from the Davis Group based in the MRC Human Immunology Unit, working with Professor Robert Tampé of Goethe University in Frankfurt, report the first structure of a T-cell receptor (TCR) bound to an activating ligand, using cryo electron microscopy. The work in Oxford was led by Mai Vuong, a Research Assistant in the Davis laboratory.

The new structure of the ligand bound, tumour specific TCR (see cover image) permitted comparisons with the structure of an unbound TCR obtained previously. This allowed the first direct test of whether the TCR has to change its shape in order to initiate signaling, after it binds to its ligand. In what will be a major surprise to many workers in the field, the new work shows that the TCR does not change its shape, unlike many other receptors (see Movie 1). This finding challenges received ideas about how immune receptors like the TCR perform their functions.

Movie 1: Atomistic molecular dynamics simulation of ligand-bound T-Cell Receptor.

The adaptive immune response, which provides pathogen- and tumor-specific immunity but can also causes diseases such as diabetes, is initiated and controlled by a subset of white blood cells, the T cells. T cells become activated when TCRs present on their surfaces bind to pathogen- or tumour-derived ligands consisting of short peptides complexed with major histocompatibility complex proteins (pMHCs) that are expressed by infected cells and tumours, or by specialised antigen presenting cells. When they bind the pMHCs, the TCRs are phosphorylated by a tyrosine kinase called Lck. This initiates a signaling cascade leading to T-cell proliferation and differentiation and, eventually, elimination of the pathogen or tumour. In effect, therefore, the TCR is the protein that “triggers” the adaptive immune response. Despite decades of research, how the TCR initiates signaling after binding pMHC proteins remains one of the great enigmas of immunology.

Previously, the structure of a TCR without a bound ligand was solved by researchers at the Harbin Institute in China. This outstanding study revealed how all the subunits in the TCR are organized but was unable to shed new light on how the TCR might function.

It was widely anticipated that the TCR would undergo spontaneous shape changes after binding the ligand, in the same manner as , for example, of G protein-coupled receptors. This would have been a way for the receptor to communicate to the cell that it had bound a ligand. Other potential explanations for receptor signaling allow for the ligand-binding αβ subunits to remain fairly rigid, and for structural changes to occur elsewhere, either spontaneously or under force. A final proposal, made many years ago by Professor Davis and his colleague Professor Anton van der Merwe of the Sir William Dunn School in Oxford, is that the TCR does not rely on shape changes or any other transformations at all. Instead, they proposed, the TCR needs only to bind passively to ligand, with signaling then being driven by extrinsic effects, i.e., the local exclusion of large tyrosine phosphatases that would otherwise counteract the activity of kinases. The new findings now firmly rule out spontaneous shape changes as the explanation for receptor signaling. It also gives new insights into receptor assembly and suggests that pMHC recognition is a cooperative process involving other cell surface proteins.

A key to the success of the project was to purify high quality TCRs from the cell surface, avoiding material from inside the cell. The trick was to use a TCR that would bind pMHC with very high affinity (kindly provided by Immunocore Ltd in Abingdon), since this would allow the good receptors at the cell surface to be ‘tagged’ with pMHC prior to purification. Ms Vuong, who was joint first author of the study, said “I like challenging projects but for a long time it seemed like this was going to be an impossible one. But it was very exciting finally to see the structure of a ligand bound TCR 12 years after we started the project. Advice from the Frankfurt laboratory on how to stabilise the complex for electron microscopy in the final step was also very important”.

Professor Davis, who was joint senior author of the study with Prof Tampé, said “I’m very grateful that Mai persevered with this project, and we were then very lucky to work with Prof Tampé, who’d done superb work on the much more complicated structure that assembles pMHC proteins inside the cell. Dr Lukas Sušac working in the Tampé lab, especially, did an outstanding job solving the structure using our material.” He went on to say, “We were all shocked by how similar the liganded and non-liganded structures were, and delighted that this discovery moves the problem of receptor signaling very significantly forward.” Prof Davis also said, “It’s important to bear in mind, however, that we solved the structure of just one high affinity TCR/pMHC complex, and more complexes, especially ones with lower affinity, need to be studied next. But this could be very challenging.” “We are excited of course that the new structure showing that the TCR is a rather passive protein supports Prof van der Merwe’s and my ideas about receptor signaling, although a big question is whether forces also contribute, which we couldn’t address in this study. But if our simple ideas are correct, they ought to be useful for enhancing the effectiveness of artificial TCRs, which are increasingly being used for cancer immunotherapy.”

The major funders for the study were the Wellcome Trust, who support Professor Davis and Ms Vuong, and the German Research Foundation and European Research Council, which fund Prof Tampé’s laboratory.

Read the full paper at Cell: Sušac et al., (2022) Structure of a fully assembled tumor-specific T-cell receptor ligated by pMHC. Cell. 185 (17: 3201-3213

 

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