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Instruments / Technical Area	Publication Details	Published
I24-Microfocus Macromolecular Crystallography	Peptide super-agonist enhances T-cell responses to melanoma Sarah A. E. Galloway , Garry Dolton , Meriem Attaf , Aaron Wall , Anna Fuller , Cristina Rius , Valentina Bianchi , Sarah Theaker , Angharad Lloyd , Marine E. Caillaud , Inge Marie Svane , Marco Donia , David K. Cole , Barbara Szomolay , Pierre Rizkallah , Andrew K. Sewell Frontiers In Immunology 10 DOI: 10.3389/fimmu.2019.00319 Diamond Proposal Number(s): [14843] Open Access Show Abstract ▼ Abstract: Recent immunotherapeutic approaches using adoptive cell therapy, or checkpoint blockade, have demonstrated the powerful anti-cancer potential of CD8 cytotoxic T-lymphocytes (CTL). While these approaches have shown great promise, they are only effective in some patients with some cancers. The potential power, and relative ease, of therapeutic vaccination against tumour associated antigens (TAA) present in different cancers has been a long sought-after approach for harnessing the discriminating sensitivity of CTL to treat cancer and has seen recent renewed interest following cancer vaccination successes using unique tumour neoantigens. Unfortunately, results with TAA-targeted “universal” cancer vaccines (UCV) have been largely disappointing. Infectious disease models have demonstrated that T-cell clonotypes that recognise the same antigen should not be viewed as being equally effective. Extrapolation of this notion to UCV would suggest that the quality of response in terms of the T-cell receptor (TCR) clonotypes induced might be more important than the quantity of the response. Unfortunately, there is little opportunity to assess the effectiveness of individual T-cell clonotypes in vivo. Here, we identified effective, persistent T-cell clonotypes in an HLA A2+ patient following successful tumour infiltrating lymphocyte (TIL) therapy. One such T-cell clone was used to generate super-agonist altered peptide ligands (APLs). Further refinement produced an APL that was capable of inducing T-cells in greater magnitude, and with improved effectiveness, from the blood of all 14 healthy donors tested. Importantly, this APL also induced T-cells from melanoma patient blood that exhibited superior recognition of the patient's own tumour compared to those induced by the natural antigen sequence. These results suggest that use of APL to skew the clonotypic quality of T-cells induced by cancer vaccination could provide a promising avenue in the hunt for the UCV “magic bullet.”	Mar 2019
B23-Circular Dichroism	Thermal Stability of Heterotrimeric pMHC Proteins as Determined by Circular Dichroism Spectroscopy Anna Fuller , Aaron Wall , Michael D. Crowther , Angharad Lloyd , Alexei Zhurov , Andrew K. Sewell , David Cole , Konrad Beck Bio-protocol 7 DOI: 10.21769/BioProtoc.2366 Diamond Proposal Number(s): [12332] Open Access Show Abstract ▼ Abstract: T cell receptor (TCR) recognition of foreign peptide fragments, presented by peptide major histocompatibility complex (pMHC), governs T-cell mediated protection against pathogens and cancer. Many factors govern T-cell sensitivity, including the affinity of the TCR-pMHC interaction and the stability of pMHC on the surface of antigen presenting cells. These factors are particularly relevant for the peptide vaccination field, in which more stable pMHC interactions could enable more effective protection against disease. Here, we discuss a method for the determination of pMHC stability that we have used to investigate HIV immune escape, T-cell sensitivity to cancer antigens and mechanisms leading to autoimmunity.	Jul 2017
B23-Circular Dichroism I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structural Mechanism Underpinning Cross-reactivity of a CD8 + T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase David K. Cole , Hugo A. Van Den Berg , Angharad Lloyd , Michael D. Crowther , Konrad Beck , Julia Ekeruche-makinde , John J. Miles , Anna M. Bulek , Garry Dolton , Andrea J. Schauenburg , Aaron Wall , Anna Fuller , Mathew Clement , Bruno Laugel , Pierre J. Rizkallah , Linda Wooldridge , Andrew K. Sewell Journal Of Biological Chemistry 292, 802 - 813 DOI: 10.1074/jbc.M116.741603 Diamond Proposal Number(s): [6232, 8096, 10462, 10049, 9308, 12332] Open Access Show Abstract ▼ Abstract: T-cell cross-reactivity is essential for effective immune surveillance but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focused antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8 T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase. The ILA1 TCR contacted its pMHC with a broad peptide binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding, the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts apparent in the structure correlated well with the level of degeneracy at different peptide positions. Thus, the ILA1 TCR was less tolerant of changes at peptide residues that were at, or adjacent to, key contact sites. This study provides new insights into the molecular mechanisms that control T-cell cross-reactivity with important implications for pathogen surveillance, autoimmunity, and transplant rejection.	Jan 2017

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