Mechanisms and manipulation of force dependent behavior in T cell biology

T 细胞生物学中力依赖性行为的机制和操纵

基本信息

批准号：
10681766
负责人：
Brian M Baker
金额：
$ 77.16万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-02 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681766
关键词：
Accounting Address Affect Affinity Antigens Automobile Driving Behavior Binding Biological Process Biology Cartoons Cell Communication Cell physiology Cellular Immunity Cellular biology Collaborations Complex Computer Simulation Disease Education Engineering Epitopes Goals Health Immune Immune system Immunologics Immunologist Immunotherapy Infection Kinetics Knowledge Libraries Ligands Lymphocytic choriomeningitis virus Measurement Membrane Mus Mutation Nature Output Peptide/MHC Complex Peptides Physics Productivity Property Proteins Publishing Science Signal Transduction Specificity Structure T cell response T-Cell Immunologic Specificity T-Lymphocyte Testing Thymus Gland Tumor Antigens Variant Viral Viral Antigens Virus Diseases Work Writing alpha-beta T-Cell Receptor cell behavior computer framework design foot frontier immunogenicity improved infancy interest lens mechanical force predictive modeling receptor response screening simulation success theories

Accounting Address Affect Affinity Antigens Automobile Driving Behavior Binding Biological Process Biology Cartoons Cell Communication Cell physiology Cellular Immunity Cellular biology Collaborations Complex Computer Simulation Disease Education Engineering Epitopes Goals Health Immune Immune system Immunologics Immunologist Immunotherapy Infection Kinetics Knowledge Libraries Ligands Lymphocytic choriomeningitis virus Measurement Membrane Mus Mutation Nature Output Peptide/MHC Complex Peptides Physics Productivity Property Proteins Publishing Science Signal Transduction Specificity Structure T cell response T-Cell Immunologic Specificity T-Lymphocyte Testing Thymus Gland Tumor Antigens Variant Viral Viral Antigens Virus Diseases Work Writing alpha-beta T-Cell Receptor cell behavior computer framework design foot frontier immunogenicity improved infancy interest lens mechanical force predictive modeling receptor response screening simulation success theories

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项目摘要

Summary TCR recognition of peptides bound and presented by MHC proteins underlies cellular immunity. TCR recognition of pMHC is most often viewed through the lens of traditional receptor-ligand theory, where cellular responses are presumed to be governed by solution binding affinities or kinetics. While this is often the case, work over the past several years has shown that complexities from mechanical forces exerted on membrane bound TCR and pMHC can profoundly influence T cell signaling. Of notable interest are catch bonds: force dependent enhancements of the lifetimes of TCR-pMHC complexes formed between interacting cells. Catch bonds can lead to large changes in signaling output and can greatly enhance T cell sensitivity. Demonstrating the importance of mechanical forces in tuning T cell responses, ligands that are recognized with strong affinity but fail to result in catch bonds yield altered or even no T cell signaling. Force-dependent behavior has been implicated in a wide range of T cell biological processes, including thymic education, responses to viral or tumor antigens, and viral escape. Although the importance of mechanical force in TCR recognition has been demonstrated, we have only a rudimentary understanding of how TCRs form catch or revert to slip bonds. We (PI Evavold) have had recent success in manipulating TCR catch bonds (published in Science this year) but this was achieved through screening libraries and without an understanding of mechanism. We thus lack predictive models for force dependent behavior in TCRs and in turn how this affects biology, which in turn impacts our ability to predict immunogenicity, assess the consequences of mutations, and hinders our ability to understand T cell specificity. Recently, however, we developed a comprehensive framework to identify, manipulate, and predict force dependent behavior in TCR-pMHC interactions. Unlike prior efforts, our framework directly addresses mechanism. Here, we will further develop, refine, and apply our framework. Our driving hypothesis is that viewing force dependent behavior through the lens of energy will provide the missing mechanistic detail of how and why catch bonds emerge in TCRs, allow their rational prediction and manipulation, and permit force considerations to be included in assessments of T cell recognition of antigen. Our three Aims are to 1) further develop our mechanistic framework for force dependent TCR behavior; 2) explain how changes to catch bonds emerge from natural variations in TCR interfaces and how catch bonds regulate T cell biology; and 3) Use rational catch bond engineering to better control viral infection in mice. Overall, the work in this proposal will illuminate the opaque mechanisms that underlie T cell mechanobiology, place catch bonds on a formal mechanistic footing, and provide the means to predict and productively manipulate TCR catch bonds and ultimately T cell biology.

概括 TCR识别由MHC蛋白结合并提出的肽是细胞免疫的基础。 TCR识别 PMHC的最常通过传统受体配体理论的镜头来查看，其中细胞反应假定由溶液结合亲和力或动力学控制。虽然经常是这种情况，但要在过去几年表明，施加在膜结合的TCR上的机械力的复杂性和 PMHC可以深刻影响T细胞信号传导。引人注目的是捕捞债券：依赖力相互作用细胞之间形成的TCR-PMHC复合物的寿命的增强。捕获纽带可以领导信号输出的巨大变化可以大大提高T细胞灵敏度。证明了重要性调谐T细胞反应的机械力，具有强亲和力但未能导致的配体的配体捕获键的产生变化甚至没有T细胞信号传导。力依赖性行为与宽阔的行为有关 T细胞生物学过程的范围，包括胸腺教育，对病毒或肿瘤抗原的反应以及病毒逃脱。尽管已经证明了机械力在TCR识别中的重要性，但我们只有对TCR如何形成捕获或恢复键的基本理解。我们（Pi vavold）最近有在操纵TCR捕获债券方面的成功（今年在科学上发表），但这是通过筛选库，而没有理解机制。因此，我们缺乏武力的预测模型 TCR中的依赖行为以及这对生物学的影响如何，从而影响我们预测的能力免疫原性，评估突变的后果，并阻碍我们理解T细胞特异性的能力。但是，最近，我们开发了一个综合框架来识别，操纵和预测力量 TCR-PMHC相互作用中的依赖行为。与先前的努力不同，我们的框架直接解决机制。在这里，我们将进一步开发，完善并应用我们的框架。我们的驾驶假设是观看通过能量镜头依赖力的行为将提供缺失的机械细节在TCR中出现捕获纽带，允许其理性的预测和操纵，并允许考虑武力的考虑要包括在评估抗原的T细胞识别中。我们的三个目标是1）进一步发展我们的力依赖性TCR行为的机械框架； 2）解释如何从 TCR界面的自然变化以及捕获键如何调节T细胞生物学； 3）使用理性捕获债券更好地控制小鼠病毒感染的工程。总体而言，该提案中的工作将照亮不透明的 T细胞机械生物学基础的机制，将捕获键放在形式的机械基础上，然后提供预测和有效地操纵TCR捕获键并最终最终T细胞生物学的手段。