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

T细胞是白色血细胞，旨在保护我们的身体免受感染。在艾滋病中，一种类型的T细胞数量少的破坏性影响太明显了。T细胞发挥极其重要的作用，因为：（1）它们协调免疫，是控制感染的关键因素;（2）它们对自然根除癌症很重要;（3）它们是成功接种疫苗的关键;（4）它们介导许多过敏反应;（5）它们在移植排斥中发挥重要作用。（6）当它们出现问题时，它们是导致自身免疫性疾病的细胞，如糖尿病、关节炎和多发性硬化症。当我们的T细胞表面的T细胞受体（TCR）分子识别称为抗原的微生物和癌症分子时，T细胞就会开始行动。据估计，我们体内有大约2500万种不同的TCR。TCR是非常重要的分子，因为它们是所有上述作用的焦点。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影响。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1，000，000，000，000，000种不同的“外来”抗原。很明显，免疫系统必须覆盖比不同T细胞更多的外来抗原。为了实现这一点，每个单独的TCR分子可以识别超过一百万种不同的可能抗原。因此，T细胞被认为是非常“交叉反应性”的。这种必要的T细胞交叉反应性是允许的，因为T细胞表面上的TCR分子可以是非常混杂的，并识别许多相似的“形状”。虽然TCR混杂使我们的T细胞能够控制感染，但它也被认为是这些细胞有时可能引起的有害影响的原因。据信，当一种对抗感染的TCR无意中混杂到足以识别我们自己的组织时，就会产生自身免疫。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就会攻击“外来”器官的原因。因此，TCR混杂是大多数人类疾病的核心。尽管其明显的重要性，还没有一个适当的尝试来检查或评估TCR混杂和T细胞交叉反应性，它使。TCR混杂的研究将需要一个经验丰富的跨学科团队的长期努力。在这项申请中，生物化学家（Andy休厄尔教授）、传染病临床医生和细胞免疫学家（大卫普莱斯教授）、兽医（琳达伍尔德里奇博士）、结构生物学家（皮埃尔里兹卡拉博士）和数学家（雨果货车登贝格博士）将运用他们在T细胞研究中的集体专业知识，首次对TCR混杂进行全面分析。该团队开发的新工具最终提供了解锁这项研究的钥匙，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，我们预计这项工作将彻底改变疫苗接种，并提供对自身免疫性疾病枯萎病的见解。简而言之，这项工作代表了基础生物学研究的罕见例子之一，具有明显的和众多的转化为临床实践的潜力。因此，我们预计这项工作将产生有价值的副产品，这些副产品将改善临床实践，并进一步加深我们对协调人类免疫的相互作用的理解。

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.