Defining how TCR strength of signal modulates Treg function

定义 TCR 信号强度如何调节 Treg 功能

• 批准号: 10707431
• 负责人: Brian D Evavold
• 金额: $ 60.74万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707431
• 关键词: Affinity; Amino Acids; Animal Model; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Binding; Biological Markers; Cell physiology; Cells; Central Nervous System; Clinical Trials; DNA; Data; Demyelinating Diseases; Demyelinations; Diagnosis; Disease; Disease Progression; Disease model; Excision; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Functional disorder; Goals; HLA-DR4 Antigen; Health; Histocompatibility Antigens Class II; Immune response; Immunosuppression; Insulin-Dependent Diabetes Mellitus; Intervention; Left; MHC Class II Genes; MHC antigen; Measures; Molecular; Multiple Sclerosis; Mutation; Myelin; Outcome; Peptide/MHC Complex; Peptides; Persons; Phenotype; Play; Pre-Clinical Model; Proteins; Publications; Regulatory T-Lymphocyte; Research Personnel; Rheumatoid Arthritis; Risk Factors; Role; Signal Transduction; Surrogate Markers; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCR Activation; Technology; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Translating; Variant; Work; biophysical properties; complementarity-determining region 3; design; effector T cell; engineered T cells; humanized mouse; in vivo; insight; novel; oligodendrocyte-myelin glycoprotein; receptor binding; response; sensor; transcriptome

Abstract/Summary Millions of people worldwide have been diagnosed with autoimmune diseases such as multiple sclerosis (MS). The hallmark of MS is progressive demyelination driven by an inappropriate immune response that attacks cells within the central nervous system. The dominant risk factor for MS, and experimental autoimmune encephalomyelitis (EAE) animal models, in addition to many other autoimmune diseases (type I diabetes, rheumatoid arthritis, etc) is specific MHC class II molecules. Since MHC class II presents peptide antigen to both CD4+ T conventional (Tconv) and regulatory T cells (Tregs), the interaction between the T cell receptor (TCR) and self peptide:MHC (pMHC) plays a pivotal role in autoimmune disease progression. The vital purpose of Tregs is to suppress immune responses against self in an antigen specific manner. Tregs recognize antigen such as myelin via their TCR, yet the fundamental measures and the underlying mechanism of TCR interaction with pMHC is unknown. Therefore, a thorough understanding of the antigen-specific reactivity of Tregs and whether this activity could be exploited has significant therapeutic potential. Here, we will dissect the interaction between TCR and myelin antigen using sensitive technologies to measure biophysical properties of TCR binding such as affinity and bond lifetimes. Of note, Tregs apply force to the bond between TCR and pMHC, which is ultimately reflected by changes in how long the proteins interact. While Treg TCRs are said to have enhanced strength of signal, mechanistically this concept is poorly defined. We discovered that suppressive Tregs apply more force to the pMHC bond than do Tconv cells. In addition, myelin-specific Tregs that fail to suppress apply lower levels of force. We therefore hypothesize that during antigen recognition, the increased magnitude of force determines the Treg suppressive phenotype. We have designed three aims to test this hypothesis that will: 1) compare antigenic binding parameters of functional versus defective Tregs; 2) determine Treg functional parameters dependent on the magnitude of force; and 3) engineer TCR sequences to decouple affinity, bond lifetime, and the level of force in response to self antigen. Thus, our project will provide novel insight into the mechanisms governing Treg function and dysfunction during demyelinating autoimmune disease. Our work will be the first to investigate various levels of force as a potent biomarker for Treg that dictates their suppressive efficacy, potency, and phenotypic stability.

摘要/概要 全世界有数百万人被诊断患有自身免疫性疾病，如多发性硬化症（MS）。 多发性硬化症的标志是由不适当的免疫反应引起的进行性脱髓鞘 中枢神经系统内的细胞。MS的主要危险因素，以及实验性自身免疫性 脑脊髓炎（EAE）动物模型，除了许多其它自身免疫疾病（I型糖尿病， 类风湿性关节炎等）是特异性MHC II类分子。由于MHC II类分子将肽抗原呈递给 CD 4+常规T细胞（Tconv）和调节性T细胞（Tconv），T细胞受体之间的相互作用 (TCR)和自身肽：MHC（pMHC）在自身免疫性疾病的进展中起着关键作用。切身 其目的是以抗原特异性方式抑制针对自身的免疫应答。THEORY识别 抗原如髓鞘通过其TCR，但TCR的基本措施和潜在机制 与pMHC的相互作用未知。因此，彻底了解抗原特异性反应性的 Tactus和是否可以利用这种活性具有显着的治疗潜力。在这里，我们将剖析 TCR和髓鞘抗原之间的相互作用，使用敏感的技术来测量 TCR结合，如亲和力和键寿命。值得注意的是，Tregs对TCR和TCR之间的结合施加力 pMHC，这最终反映在蛋白质相互作用时间的变化上。虽然据说Treg TCR 具有增强的信号强度，但从机械上讲，这个概念定义不好。我们发现 抑制性Tconv细胞比Tconv细胞对pMHC键施加更大的力。此外，髓鞘特异性TdR 不能抑制的施加较低水平的力。因此，我们假设在抗原识别过程中， 增加的力的大小决定了Treg抑制性表型。我们设计了三个目标， 测试该假设将：1）比较功能性与缺陷性TCLs的抗原结合参数; 2） 根据力的大小确定Treg功能参数;和3）工程化TCR序列 以解耦亲和力、键寿命和响应于自身抗原的力的水平。因此，我们的项目将 为脱髓鞘过程中调节Treg功能和功能障碍的机制提供了新的见解 自身免疫性疾病我们的工作将是第一个调查各种水平的力量作为一个有效的生物标志物， 调节性T细胞决定了它们的抑制功效、效力和表型稳定性。