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2. HLA A*24:02-restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes

Author

Dolton, Garry, Bulek, Anna, Wall, Aaron, Thomas, Hannah, Hopkins, Jade R., Rius, Cristina, Galloway, Sarah A.E., Whalley, Thomas, Tan, Li Rong, Morin, Theo, Omidvar, Nader, Fuller, Anna, Topley, Katie, Hasan, Md. Samiul, Jain, Shikha, D'Souza, Nirupa, Hodges-Hoyland, Thomas, Spiller, Owen B., Kronenberg-Versteeg, Deborah, Szomolay, Barbara, van den Berg, Hugo A., Jones, Lucy C., Peakman, Mark, Cole, David K., Rizkallah, Pierre J., and Sewell, Andrew K.

Subjects
T cells -- Receptors, Medical research, Medicine, Experimental, HLA histocompatibility antigens -- Health aspects, Antigen receptors, T cell -- Health aspects, Type 1 diabetes -- Physiological aspects, Bacterial proteins -- Physiological aspects, Peptides -- Health aspects, Histocompatibility antigens -- Health aspects
Abstract

[CD8.sup.+] T cells destroy insulin-producing pancreatic [beta] cells in type 1 diabetes through HLA class I- restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24* healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease., Introduction Multiple lines of evidence show that type 1 diabetes (T1D) develops due to [CD8.sup.+] T cell-mediated destruction of insulin-producing pancreatic [beta] cells. Human leukocyte antigen class I (HLA-I), the [...]

Published
2024
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3. A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation

Author

Hulin-Curtis, Sarah, Geary, James K., MacLachlan, Bruce J., Altmann, Danny M., Baillon, Laury, Cole, David K., Greenshields-Watson, Alex, Hesketh, Sophie J., Humphreys, Ian R., Jones, Ian M., Lauder, Sarah N., Mason, Georgina H., Smart, Kathryn, Scourfield, D. Oliver, Scott, Jake, Sukhova, Ksenia, Stanton, Richard J., Wall, Aaron, Rizkallah, Pierre J., Barclay, Wendy S., Gallimore, Awen, and Godkin, Andrew

Published
2024
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7. Structural and biophysical characterisation of T-cell receptor cross-reactivity in health and disease

Author

Wall, Aaron

Abstract

Background - T-cells are a crucial component of the adaptive immune system, responsible for host immunity to numerous pathogens. T-cells recognise pathogenic peptides presented on target cells via the T-cell receptor. To facilitate comprehensive immune coverage, T-cell receptors can 'cross-react' with multiple pathogenic peptides. However, T-cell crossreactivity has also been implicated in autoimmune disease, where recognition of a pathogenic epitope can trigger autoimmune recognition. While the biochemical mechanism governing T-cell cross-reactivity has been previously investigated, many of these studies involve non-clinically relevant T-cells. To understand the physiological consequences of Tcell cross-reactivity and its biochemical mechanisms, clinically relevant T-cells needed to be studied. Results - I have studied several T-cells which have been implicated in disease. The first, the ST8 T-cell, had previously been shown to cross-react with multiple tumour-associated antigens, resulting in a more potent T-cell response against tumour cells. I presented structural evidence that the ST8 T-cell receptor recognises these different peptide residues via conserved hotspot residues present on its target peptides. I also showed that this hotspot recognition was present in another cancer-specific T-cell, MEL5, which can recognise the same tumour-associated antigens as ST8. These findings demonstrate a new mechanism by which T-cells could respond to tumour cells, thus highlighting a clinical benefit to T-cell crossreactivity. To address the potential drawbacks of T-cell cross-reactivity I also studied several T-cells clones (4C6, InsB4, and NLV2D9) which have been implicated in type 1 diabetes. Using a combinatorial library screen, I identified multiple pathogenic epitopes that were recognised by 4C6 and InsB4 which may act as a pathogenic trigger. Structural data showed these T-cells also utilise hotspot recognition to achieve cross-reactivity between peptides.

Published
2021

8. Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy

Author

Dolton, Garry, Rius, Cristina, Wall, Aaron, Szomolay, Barbara, Bianchi, Valentina, Galloway, Sarah A.E., Hasan, Md Samiul, Morin, Théo, Caillaud, Marine E., Thomas, Hannah L., Theaker, Sarah, Tan, Li Rong, Fuller, Anna, Topley, Katie, Legut, Mateusz, Attaf, Meriem, Hopkins, Jade R., Behiry, Enas, Zabkiewicz, Joanna, Alvares, Caroline, Lloyd, Angharad, Rogers, Amber, Henley, Peter, Fegan, Christopher, Ottmann, Oliver, Man, Stephen, Crowther, Michael D., Donia, Marco, Svane, Inge Marie, Cole, David K., Brown, Paul E., Rizkallah, Pierre, and Sewell, Andrew K.

Published
2023
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9. Evaluation of the potential for nine established and emerging interventions to reduce soil carbon losses and increase stocks in grazing systems: A case study for Aotearoa New Zealand.

Author

Whitehead, David, McNally, Samuel R., Graham, Scott L., Pronger, Jack, Wall, Aaron M., Isson, Terry, Beare, Mike H., Tozer, Katherine N., Doole, Graeme J., Murray, Shevani, Mudge, Paul L., and Schipper, Louis A.

Subjects
GREENHOUSE gases, SOIL management, RANGE management, SOIL classification, ORGANIC farming
Abstract

This article reviews nine soil carbon interventions to reduce soil carbon losses or increase stocks in grazing management systems, using their potential application in Aotearoa New Zealand (A‐NZ) as a case study. The interventions are classified into three strategies: (1) increasing carbon inputs through deep‐rooting and diverse species grasslands, reducing forage cropping and deferred grazing management; (2) increasing protection of carbon stocks by water table management on organic soils, reducing cropping on organic soils, full inversion tillage grassland renewal, the addition of clay minerals and enhanced rock weathering and (3) the adoption of integrated systems including establishing tree clusters into grasslands and agroforestry. We estimated the land area where these interventions could realistically be implemented in A‐NZ and assessed their potential impact on mitigating national overall agricultural greenhouse gas emissions. The potential impact of each intervention ranged from <1% to 2.5% of national agricultural greenhouse gas emissions over 20 years. However, confidence in these approaches is hindered by a lack of research data where these approaches have been tested for different soil types and conditions. Notably, water table management, which reduces carbon loss from organic soils, was the only intervention that could achieve moderate, short‐ and long‐term impacts with a confidence level assessed as 'likely'. We conclude that reducing further soil carbon losses and achieving modest increases in soil carbon stocks are possible but will require economic and political incentives that encourage the integration of multiple interventions at the farm scale. [ABSTRACT FROM AUTHOR]

Published
2024
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12. A Targeted Amino Acid Mutation in Influenza a Virus Universal Epitope Transforms Immunogenicity and Protective Immunity via CD4 T Cell Activation

Author

Hulin-Curtis, Sarah Louise, primary, Geary, James, additional, MacLachlan, Bruce, additional, Altmann, Daniel, additional, Baillon, Laury, additional, Cole, David, additional, Greenshields-Watson, Alexander, additional, Hesketh, Sophie, additional, Humphreys, Ian R., additional, Jones, Ian, additional, Lauder, Sarah, additional, Mason, Georgina, additional, Smart, Kathryn, additional, Scourfield, Oliver, additional, Scott, Jake, additional, Sukhova, Ksenia, additional, Stanton, Richard J., additional, Wall, Aaron, additional, Rizkallah, Pierre, additional, Barclay, Wendy S., additional, Gallimore, Awen, additional, and Godkin, Andrew, additional

Published
2023
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16. Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope

Author

Dolton, Garry, Rius, Cristina, Hasan, Md Samiul, Wall, Aaron, Szomolay, Barbara, Behiry, Enas, Whalley, Thomas, Southgate, Joel, Fuller, Anna, COVID-19 Genomics UK (COG-UK) consortium, Morin, Théo, Topley, Katie, Tan, Li Rong, Goulder, Philip JR, Spiller, Owen B, Rizkallah, Pierre J, Jones, Lucy C, Connor, Thomas R, Sewell, Andrew K, Sewell, Andrew K [0000-0003-3194-3135], and Apollo - University of Cambridge Repository

Subjects
HLA-A Antigens, SARS-CoV-2, peptide-HLA, Histocompatibility Antigens Class I, immune escape, Humans, COVID-19, T cell, Epitopes, T-Lymphocyte, phylogenetic, T cell receptors, CD8-Positive T-Lymphocytes, CD8 T cell
Abstract

We studied the prevalent cytotoxic CD8 T cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein269-277 epitope (sequence YLQPRTFLL) via the most frequent human leukocyte antigen (HLA) class I worldwide, HLA A∗02. The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as "variants of concern," was not recognized by the large CD8 T cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T cell receptors. Viral escape at prevalent T cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focused on a single protein such as SARS-CoV-2 Spike, providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T cell escape in new SARS-CoV-2 variants.

Published
2022

17. Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope

Author

Dolton, Garry, primary, Rius, Cristina, additional, Hasan, Md Samiul, additional, Wall, Aaron, additional, Szomolay, Barbara, additional, Behiry, Enas, additional, Whalley, Thomas, additional, Southgate, Joel, additional, Fuller, Anna, additional, Morin, Théo, additional, Topley, Katie, additional, Tan, Li Rong, additional, Goulder, Philip J.R., additional, Spiller, Owen B., additional, Rizkallah, Pierre J., additional, Jones, Lucy C., additional, Connor, Thomas R., additional, and Sewell, Andrew K., additional

Published
2022
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18. Long-Term Portfolio Projects to Teach and Assess Culture Learning in the Secondary Spanish Classroom: Shifting the Area of Expertise

Author

Byrd, David R. and Wall, Aaron

Abstract

Secondary teachers often find it difficult to include the study of culture in their classes. Long-term cultural portfolios (LCPs) provide a method of allowing teachers to address culture in a substantial manner by allowing teachers to join students in the exploration of cultural topics. Teachers first select a cultural artifact, determine the themes associated with it, create activities to scaffold student learning, allow students to present their findings and, finally, have students reflect on the project as a whole. By providing students with significant time with the cultural artifact, they are not only able to examine the products and/or practices of a culture in-depth, but also gain insight into the perspectives from which the artifact emanates.

Published
2009

19. Bridge to the future: Important lessons from 20 years of ecosystem observations made by the OzFlux network

Author

Beringer, Jason, Moore, Caitlin E., Cleverly, Jamie, Campbell, David I., Cleugh, Helen, De Kauwe, Martin G., Kirschbaum, Miko U. F., Griebel, Anne, Grover, Sam, Huete, Alfredo, Hutley, Lindsay B., Laubach, Johannes, Van Niel, Tom, Arndt, Stefan K., Bennett, Alison C., Cernusak, Lucas A., Eamus, Derek, Ewenz, Cacilia M., Goodrich, Jordan P., Jiang, Mingkai, Hinko-Najera, Nina, Isaac, Peter, Hobeichi, Sanaa, Knauer, Jürgen, Koerber, Georgia R., Liddell, Michael, Ma, Xuanlong, Macfarlane, Craig, McHugh, Ian D., Medlyn, Belinda E., Meyer, Wayne S., Norton, Alexander J., Owens, Jyoteshna, Pitman, Andy, Pendall, Elise, Prober, Suzanne M., Ray, Ram L., Restrepo-Coupe, Natalia, Rifai, Sami W., Rowlings, David, Schipper, Louis, Silberstein, Richard P., Teckentrup, Lina, Thompson, Sally E., Ukkola, Anna M., Wall, Aaron, Wang, Ying-Ping, Wardlaw, Tim J., Woodgate, William, Beringer, Jason, Moore, Caitlin E., Cleverly, Jamie, Campbell, David I., Cleugh, Helen, De Kauwe, Martin G., Kirschbaum, Miko U. F., Griebel, Anne, Grover, Sam, Huete, Alfredo, Hutley, Lindsay B., Laubach, Johannes, Van Niel, Tom, Arndt, Stefan K., Bennett, Alison C., Cernusak, Lucas A., Eamus, Derek, Ewenz, Cacilia M., Goodrich, Jordan P., Jiang, Mingkai, Hinko-Najera, Nina, Isaac, Peter, Hobeichi, Sanaa, Knauer, Jürgen, Koerber, Georgia R., Liddell, Michael, Ma, Xuanlong, Macfarlane, Craig, McHugh, Ian D., Medlyn, Belinda E., Meyer, Wayne S., Norton, Alexander J., Owens, Jyoteshna, Pitman, Andy, Pendall, Elise, Prober, Suzanne M., Ray, Ram L., Restrepo-Coupe, Natalia, Rifai, Sami W., Rowlings, David, Schipper, Louis, Silberstein, Richard P., Teckentrup, Lina, Thompson, Sally E., Ukkola, Anna M., Wall, Aaron, Wang, Ying-Ping, Wardlaw, Tim J., and Woodgate, William

Abstract

In 2020, the Australian and New Zealand flux research and monitoring network, OzFlux, celebrated its 20th anniversary by reflecting on the lessons learned through two decades of ecosystem studies on global change biology. OzFlux is a network not only for ecosystem researchers, but also for those ‘next users’ of the knowledge, information and data that such networks provide. Here, we focus on eight lessons across topics of climate change and variability, disturbance and resilience, drought and heat stress and synergies with remote sensing and modelling. In distilling the key lessons learned, we also identify where further research is needed to fill knowledge gaps and improve the utility and relevance of the outputs from OzFlux. Extreme climate variability across Australia and New Zealand (droughts and flooding rains) provides a natural laboratory for a global understanding of ecosystems in this time of accelerating climate change. As evidence of worsening global fire risk emerges, the natural ability of these ecosystems to recover from disturbances, such as fire and cyclones, provides lessons on adaptation and resilience to disturbance. Drought and heatwaves are common occurrences across large parts of the region and can tip an ecosystem's carbon budget from a net CO2 sink to a net CO2 source. Despite such responses to stress, ecosystems at OzFlux sites show their resilience to climate variability by rapidly pivoting back to a strong carbon sink upon the return of favourable conditions. Located in under-represented areas, OzFlux data have the potential for reducing uncertainties in global remote sensing products, and these data provide several opportunities to develop new theories and improve our ecosystem models. The accumulated impacts of these lessons over the last 20 years highlights the value of long-term flux observations for natural and managed systems. A future vision for OzFlux includes ongoing and newly developed synergies with ecophysiologists, ecologists

Published
2022

20. Oral history interview with Aaron Wall, 2022

Author

Wall, Aaron, Lawrimore, Erin, Wall, Aaron, and Lawrimore, Erin

Abstract

Along with partners Aaron Sizemore and Eric Peck, Aaron Wall opened Radar Brewing in Winston-Salem, NC in January 2020. In this interview, Wall details his prior brewing experiences at Natty Greene's Brewing in Greensboro, Foothills Brewing in Winston-Salem, and Wicked Weed Brewing in Asheville. He also talks about being both a student and instructor in the fermentation sciences program at Rockingham Community College. He discusses the work that went into opening Radar as well as the changes and challenges brought about by the COVID-19 pandemic.

Published
2022

21. Bridge to the future: Important lessons from 20 years of ecosystem observations made by the OzFlux network

Author

Beringer, Jason, primary, Moore, Caitlin E., additional, Cleverly, Jamie, additional, Campbell, David I., additional, Cleugh, Helen, additional, De Kauwe, Martin G., additional, Kirschbaum, Miko U. F., additional, Griebel, Anne, additional, Grover, Sam, additional, Huete, Alfredo, additional, Hutley, Lindsay B., additional, Laubach, Johannes, additional, Van Niel, Tom, additional, Arndt, Stefan K., additional, Bennett, Alison C., additional, Cernusak, Lucas A., additional, Eamus, Derek, additional, Ewenz, Cacilia M., additional, Goodrich, Jordan P., additional, Jiang, Mingkai, additional, Hinko‐Najera, Nina, additional, Isaac, Peter, additional, Hobeichi, Sanaa, additional, Knauer, Jürgen, additional, Koerber, Georgia R., additional, Liddell, Michael, additional, Ma, Xuanlong, additional, Macfarlane, Craig, additional, McHugh, Ian D., additional, Medlyn, Belinda E., additional, Meyer, Wayne S., additional, Norton, Alexander J., additional, Owens, Jyoteshna, additional, Pitman, Andy, additional, Pendall, Elise, additional, Prober, Suzanne M., additional, Ray, Ram L., additional, Restrepo‐Coupe, Natalia, additional, Rifai, Sami W., additional, Rowlings, David, additional, Schipper, Louis, additional, Silberstein, Richard P., additional, Teckentrup, Lina, additional, Thompson, Sally E., additional, Ukkola, Anna M., additional, Wall, Aaron, additional, Wang, Ying‐Ping, additional, Wardlaw, Tim J., additional, and Woodgate, William, additional

Published
2022
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29. Author Correction:Positive functional synergy of structurally integrated artificial protein dimers assembled by Click chemistry (Communications Chemistry, (2019), 2, 1, (83), 10.1038/s42004-019-0185-5)

Author

Worthy, Harley L., Auhim, Husam Sabah, Jamieson, W. David, Pope, Jacob R., Wall, Aaron, Batchelor, Robert, Johnson, Rachel L., Watkins, Daniel W., Rizkallah, Pierre, Castell, Oliver K., and Jones, D. Dafydd

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

31. CD4+ T Cells Recognize Conserved Influenza A Epitopes through Shared Patterns of V-Gene Usage and Complementary Biochemical Features

Author

Greenshields-Watson, Alexander, primary, Attaf, Meriem, additional, MacLachlan, Bruce J., additional, Whalley, Thomas, additional, Rius, Cristina, additional, Wall, Aaron, additional, Lloyd, Angharad, additional, Hughes, Hywel, additional, Strange, Kathryn E., additional, Mason, Georgina H., additional, Schauenburg, Andrea J., additional, Hulin-Curtis, Sarah L., additional, Geary, James, additional, Chen, Yuan, additional, Lauder, Sarah N., additional, Smart, Kathryn, additional, Vijaykrishna, Dhanasekaran, additional, Grau, Miguel L., additional, Shugay, Mikhail, additional, Andrews, Robert, additional, Dolton, Garry, additional, Rizkallah, Pierre J., additional, Gallimore, Awen M., additional, Sewell, Andrew K., additional, Godkin, Andrew J., additional, and Cole, David K., additional

Published
2020
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36. GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope

Author

Whalley, Thomas, primary, Dolton, Garry, additional, Brown, Paul E., additional, Wall, Aaron, additional, Wooldridge, Linda, additional, van den Berg, Hugo, additional, Fuller, Anna, additional, Hopkins, Jade R., additional, Crowther, Michael D., additional, Attaf, Meriem, additional, Knight, Robin R., additional, Cole, David K., additional, Peakman, Mark, additional, Sewell, Andrew K., additional, and Szomolay, Barbara, additional

Published
2020
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38. Peptide Super-Agonist Enhances T-Cell Responses to Melanoma

Author

Galloway, Sarah A E, Dolton, Garry, Attaf, Meriem, Wall, Aaron, Fuller, Anna, Rius, Cristina, Bianchi, Valentina, Theaker, Sarah, Lloyd, Angharad, Caillaud, Marine E, Svane, Inge Marie, Donia, Marco, Cole, David K, Szomolay, Barbara, Rizkallah, Pierre, Sewell, Andrew K, Galloway, Sarah A E, Dolton, Garry, Attaf, Meriem, Wall, Aaron, Fuller, Anna, Rius, Cristina, Bianchi, Valentina, Theaker, Sarah, Lloyd, Angharad, Caillaud, Marine E, Svane, Inge Marie, Donia, Marco, Cole, David K, Szomolay, Barbara, Rizkallah, Pierre, and Sewell, Andrew K

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."

Published
2019

39. A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+T cell activation

Author

Hulin-Curtis, Sarah, Geary, James K., MacLachlan, Bruce J., Altmann, Danny M., Baillon, Laury, Cole, David K., Greenshields-Watson, Alex, Hesketh, Sophie J., Humphreys, Ian R., Jones, Ian M., Lauder, Sarah N., Mason, Georgina H., Smart, Kathryn, Scourfield, D. Oliver, Scott, Jake, Sukhova, Ksenia, Stanton, Richard J., Wall, Aaron, Rizkallah, Pierre J., Barclay, Wendy S., Gallimore, Awen, and Godkin, Andrew

Abstract

CD4+T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues (PFRs), to “tune” CD4+T cell responses within an in vivomodel system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4+and CD8+T cells prior to re-infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4+T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.

Published
2024
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41. Peptide Super-Agonist Enhances T-Cell Responses to Melanoma

Author

Galloway, Sarah A. E., primary, Dolton, Garry, additional, Attaf, Meriem, additional, Wall, Aaron, additional, Fuller, Anna, additional, Rius, Cristina, additional, Bianchi, Valentina, additional, Theaker, Sarah, additional, Lloyd, Angharad, additional, Caillaud, Marine E., additional, Svane, Inge Marie, additional, Donia, Marco, additional, Cole, David K., additional, Szomolay, Barbara, additional, Rizkallah, Pierre, additional, and Sewell, Andrew K., additional

Published
2019
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44. Structural mechanism underpinning cross-reactivity of a CD8+ T-cell clone that recognises a peptide derived from human telomerase reverse transcriptase

Author

Cole, David K., Berg, Hugo van den, Lloyd, Angharad, Crowther, Michael D., Beck, Konrad, Ekeruche-Makinde, Julia, Miles, John J., Bulek, Anna M., Dolton, Garry, Schauenburg, Andrea J., Wall, Aaron, Fuller, Anna, Clement, Mathew, Laugel, Bruno, Rizkallah, Pierre J., Wooldridge, Linda, and Sewell, Andrew K.

Subjects
Biochemistry & Molecular Biology, Immunology, T cells, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Cross Reactions, telomerase, BETA-CELLS, CLASS-I, BINDING, Humans, QD, tumor immunology, ANTIGEN RECOGNITION, SPECIFICITY, Cells, Cultured, AFFINITY, X-ray crystallography, CARDIOVASCULAR TOXICITY, Science & Technology, RECEPTOR RECOGNITION, 11 Medical And Health Sciences, 06 Biological Sciences, T cell degeneracy, R1, MAJOR HISTOCOMPATIBILITY COMPLEX, peptides, T cell receptor, 03 Chemical Sciences, Life Sciences & Biomedicine, surface plasmon resonance (SPR), TCR
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 focussed 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 (hTERT). 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.

Published
2017

50. CD4+T Cells Recognize Conserved Influenza A Epitopes through Shared Patterns of V-Gene Usage and Complementary Biochemical Features

Author

Greenshields-Watson, Alexander, Attaf, Meriem, MacLachlan, Bruce J., Whalley, Thomas, Rius, Cristina, Wall, Aaron, Lloyd, Angharad, Hughes, Hywel, Strange, Kathryn E., Mason, Georgina H., Schauenburg, Andrea J., Hulin-Curtis, Sarah L., Geary, James, Chen, Yuan, Lauder, Sarah N., Smart, Kathryn, Vijaykrishna, Dhanasekaran, Grau, Miguel L., Shugay, Mikhail, Andrews, Robert, Dolton, Garry, Rizkallah, Pierre J., Gallimore, Awen M., Sewell, Andrew K., Godkin, Andrew J., and Cole, David K.

Abstract

T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated by the highly variable T cell receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes by using identical or highly related TCRs expressed on CD8+T cells. Characterization of these TCRs has extended our understanding of the molecular mechanisms that govern the recognition of peptide-HLA. However, few examples exist for CD4+T cells. Here, we investigate CD4+T cell responses to the internal proteins of the influenza A virus that correlate with protective immunity. We identify five internal epitopes that are commonly recognized by CD4+T cells in five HLA-DR1+subjects and show conservation across viral strains and zoonotic reservoirs. TCR repertoire analysis demonstrates several shared gene usage biases underpinned by complementary biochemical features evident in a structural comparison. These epitopes are attractive targets for vaccination and other T cell therapies.

Published
2020
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