Comprehensive analysis of T-cell receptor degeneracy and T-cell crossreactivity

T细胞受体简并性和T细胞交叉反应性综合分析

• 批准号: BB/H001085/1
• 负责人: Andrew Sewell
• 金额: $ 373.7万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH001085%2F1
• 关键词: Comprehensive; analysis; cell; receptor; degeneracy

T-cells are white blood cells designed to protect our bodies from infection. The devastating effects of low numbers of just one type of T-cell are all too evident in HIV-AIDS. T-cells perform extremely important roles because: (1) They orchestrate immunity and are key elements in the control of infection; (2) They are important for the natural eradication of cancer; (3) They hold the key to successful vaccination; (4) They mediate many allergic reactions; (5) They play a substantial role in transplant rejection; and, (6) When they go wrong, they are the cells that cause autoimmune diseases such as diabetes, arthritis and multiple sclerosis. Our T-cells spring into action when the molecules on their surface called T-cell receptors (TCRs) recognize bits of microbes and cancer molecules called antigens. It is estimated that we have T-cells with about 25 million different TCRs in our bodies. TCRs are extremely important molecules because they are at the very focal point of all the above roles. In addition, TCRs are largely responsible for how our immune systems 'learn' and therefore protect us from subsequent exposures to the same germs. In order to deal with all possible infections, our T-cells have to be able to recognize more than 1,000,000,000,000,000 different 'foreign' antigens that we could encounter. It is clear that the immune system has to cover many more foreign antigens than it has different T-cells. To achieve this, each individual TCR molecule may recognize more than a million different possible antigens. As a result, T-cells are said to be extremely 'crossreactive'. This essential T-cell crossreactivity is permissible because the TCR molecule on the T-cell surface can be tremendously promiscuous and recognize many similar 'shapes'. While TCR promiscuity allows our T-cells to control infection, it is also thought to be responsible for the harmful effects these cells can sometimes cause. Autoimmunity is believed to arise when a TCR that is raised to fight infection is inadvertently promiscuous enough to recognize our own tissue. This promiscuous TCR recognition can also result in allergic reactions and is responsible for why our immune cells attack a 'foreign' organ in the first week after it is transplanted. Thus, TCR promiscuity sits at the very heart of most human disease. Despite its obvious importance, there has never yet been a proper attempt to examine or assess TCR promiscuity and the T-cell crossreactivity it enables. Study of TCR promiscuity will require a longer-term effort by an experienced and interdisciplinary team. In this application, a biochemist (Professor Andy Sewell) an infectious diseases clinician and cellular immunologist (Professor David Price), a veterinarian (Dr. Linda Wooldridge), a structure biologist (Dr. Pierre Rizkallah) and a mathematician (Dr. Hugo van den Berg) will apply their collective expertise in T-cell research to undertake a comprehensive analysis of TCR promiscuity for the first time. New tools that this team has developed have finally provided the keys to unlock this study and make this application especially timely. The potential applications and benefits of this work are immense. We have already built TCRs that are promiscuous enough to see all known immune escape variants of the HIV virus. We have further built TCRs that have better 'shapes' for detecting and eliminating cancer. In addition, we expect that this work will revolutionize vaccination and provide insights into the blight of autoimmune disease. In short, this work represents one of those rare examples of basic biological research that has obvious and numerous potentials for translation to clinical practice. As such, we anticipate that this work will generate valuable spin-offs that will improve clinical practice in addition to furthering our understanding of the very interaction that orchestrates human immunity.

t细胞是一种白细胞，用来保护我们的身体免受感染。一种t细胞数量过少所造成的毁灭性影响在hiv -艾滋病中非常明显。t细胞发挥着极其重要的作用，因为：(1)它们协调免疫，是控制感染的关键因素；(2)对自然根除癌症很重要；(3)它们是疫苗接种成功的关键；(4)介导多种过敏反应；(5)它们在移植排斥反应中起重要作用；(6)当它们出现问题时，它们是导致自身免疫性疾病（如糖尿病、关节炎和多发性硬化症）的细胞。当t细胞表面的分子t细胞受体（tcr）识别出微小的微生物和称为抗原的癌症分子时，我们的t细胞就会开始行动。据估计，我们体内的t细胞含有大约2500万个不同的tcr。tcr是非常重要的分子，因为它们是上述所有作用的焦点。此外，tcr在很大程度上负责我们的免疫系统如何“学习”，从而保护我们免受随后接触相同细菌的伤害。为了应对所有可能的感染，我们的t细胞必须能够识别我们可能遇到的超过1000,000,000,000,000种不同的“外来”抗原。很明显，免疫系统必须覆盖的外来抗原比它拥有的不同t细胞要多得多。为了实现这一点，每个单独的TCR分子可以识别超过100万种不同的可能抗原。因此，人们认为t细胞具有极强的“交叉反应性”。这种基本的t细胞交叉反应是允许的，因为t细胞表面的TCR分子可以非常混杂，并识别许多相似的“形状”。虽然TCR混杂允许我们的t细胞控制感染，但它也被认为是这些细胞有时会造成有害影响的原因。自身免疫被认为是当一个用来对抗感染的TCR在不经意间混杂到足以识别我们自己的组织时产生的。这种混杂的TCR识别也会导致过敏反应，这也是为什么我们的免疫细胞在移植后的第一周攻击“外来”器官的原因。因此，TCR滥交是大多数人类疾病的核心。尽管TCR的重要性显而易见，但迄今为止还没有适当的尝试来检查或评估TCR的混杂性和它所导致的t细胞交叉反应性。研究TCR滥交将需要一个有经验的跨学科团队的长期努力。在这项申请中，一位生物化学家（安迪·休威尔教授）、一位传染病临床医生和细胞免疫学家（大卫·普莱斯教授）、一位兽医（琳达·伍尔德里奇博士）、一位结构生物学家（皮埃尔·里兹卡拉博士）和一位数学家（雨果·范登伯格博士）将运用他们在t细胞研究方面的集体专业知识，首次对TCR滥交进行全面分析。该团队开发的新工具最终为解锁这项研究提供了钥匙，并使该应用程序特别及时。这项工作的潜在应用和好处是巨大的。我们已经建立了足够混杂的tcr，可以看到所有已知的HIV病毒的免疫逃逸变体。我们进一步构建了具有更好“形状”的tcr，用于检测和消除癌症。此外，我们期望这项工作将彻底改变疫苗接种，并为自身免疫性疾病的枯萎提供见解。简而言之，这项工作代表了那些罕见的基础生物学研究的例子之一，具有明显的和众多的潜力转化为临床实践。因此，我们预计这项工作将产生有价值的副产品，除了进一步加深我们对协调人体免疫的相互作用的理解外，还将改善临床实践。

项目成果

Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes.

1型糖尿病中CD8（+）T细胞杀死人β细胞的结构基础。

• DOI: 10.1038/ni.2206
• 发表时间: 2012-01-15
• 期刊: Nature immunology
• 影响因子: 30.5

Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition.

• DOI: 10.4049/jimmunol.1000629
• 发表时间: 2010-08-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Cole DK;Edwards ES;Wynn KK;Clement M;Miles JJ;Ladell K;Ekeruche J;Gostick E;Adams KJ;Skowera A;Peakman M;Wooldridge L;Price DA;Sewell AK
• 通讯作者: Sewell AK

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor.

• DOI: 10.1073/pnas.2019639118
• 发表时间: 2021-07-20
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Clement M;Knezevic L;Dockree T;McLaren JE;Ladell K;Miners KL;Llewellyn-Lacey S;Rubina A;Francis O;Cole DK;Sewell AK;Bridgeman JS;Price DA;van den Berg HA;Wooldridge L
• 通讯作者: Wooldridge L

A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen.

• DOI: 10.1074/jbc.m115.707414
• 发表时间: 2016-04-22
• 期刊: The Journal of biological chemistry
• 作者: Bianchi V;Bulek A;Fuller A;Lloyd A;Attaf M;Rizkallah PJ;Dolton G;Sewell AK;Cole DK
• 通讯作者: Cole DK

TCR/pMHC Optimized Protein crystallization Screen.

• DOI: 10.1016/j.jim.2012.06.007
• 发表时间: 2012-08-31
• 期刊: JOURNAL OF IMMUNOLOGICAL METHODS
• 影响因子: 2.2
• 作者: Bulek, Anna M.;Madura, Florian;Fuller, Anna;Holland, J.;Schauenburg, Andrea J. A.;Sewell, Andrew K.;Rizkallah, Pierre J.;Cole, David K.
• 通讯作者: Cole, David K.