Milighetti, Martina;
(2023)
Analysis of T cell receptor sequence and structure to understand the drivers of antigen specificity.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
T cells are key mediators of adaptive immunity. They recognise foreign antigens presented on major histocompatibility complexes (pMHCs) using the T cell receptor (TCR). The TCR is virtually unique to a T cell, and can act as a barcode to identify immune responses to antigen. TCR sequencing has allowed us to track the T cell response, and predict TCR-pMHC interaction. However, the interaction between a TCR and pMHC is a biophysical one, mediated by the rules of protein-protein interactions. In this thesis, we tried to bridge the gap between TCR sequence and structure, to gain further insights into TCR specificity. First, we retrieved all publicly available TCR-pMHC crystal structures and asked whether common rules of binding could be identified. Having found common features, we hypothesised that structural information could be used to create a classifier which would assign the correct antigen to each TCR. We built an SVM-based classifier using existing homology-modelling tools and showed modest performance, but comparable to what can be achieved by sequence-based models. By looking at published structures, we also hypothesised that intra- and inter-chain contacts shape the TCR binding site for antigen, by constraining the available conformations for the CDR loops. We find that these interactions shape epitope-specific repertoires at the sequence level. To further validate these observations, we created TCR constructs where single regions were edited. All our edits ablated pMHC binding, demonstrating the importance of all components of the TCR in binding pMHC. Finally, we analysed the relationship between the TCRα and β chain sequences and showed that there is a detectable and learnable co-evolution signal between the two. Overall, we show that analysis of TCR structure can help better understand TCR sequences, and unlock new possibilities to analyse TCR sequencing datasets.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Analysis of T cell receptor sequence and structure to understand the drivers of antigen specificity |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10181469 |
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