Defining how TCR strength of signal modulates Treg function

定义 TCR 信号强度如何调节 Treg 功能

基本信息

批准号：
10608466
负责人：
Brian D Evavold
金额：
$ 63.27万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10608466
关键词：
Address Affinity Amino Acids Animal Model Antigens Autoantigens Autoimmune Diseases Autoimmune Responses Binding Biological Markers Cell physiology Cells 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 Neuraxis 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 base 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

项目摘要

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/总结全世界有数百万人被诊断患有多发性硬化症 (MS) 等自身免疫性疾病。 MS 的标志是由不适当的免疫反应驱动的进行性脱髓鞘，攻击中枢神经系统内的细胞。 MS 的主要危险因素和实验性自身免疫脑脊髓炎 (EAE) 动物模型，以及许多其他自身免疫性疾病（I 型糖尿病、类风湿性关节炎等）是特定的 MHC II 类分子。由于 MHC II 类呈递肽抗原 CD4+ 常规 T 细胞 (Tconv) 和调节性 T 细胞 (Treg)，T 细胞受体之间的相互作用 (TCR) 和自身肽：MHC (pMHC) 在自身免疫性疾病进展中发挥着关键作用。至关重要的 Tregs 的目的是以抗原特异性方式抑制针对自身的免疫反应。 Tregs 识别髓磷脂等抗原通过TCR，但TCR的基本措施和潜在机制与 pMHC 的相互作用尚不清楚。因此，全面了解抗原特异性反应性 Tregs 以及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 和髓磷脂抗原之间的相互作用，使用敏感技术测量生物物理特性 TCR 结合，例如亲和力和键寿命。值得注意的是，Tregs 对 TCR 和 TCR 之间的键施加作用力。 pMHC，最终通过蛋白质相互作用时间的变化来反映。虽然 Treg TCR 据说增强了信号强度，从机制上讲，这个概念的定义很差。我们发现抑制性 Tregs 对 pMHC 键施加的力比 Tconv 细胞更大。此外，髓磷脂特异性Tregs 未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，力量的增加决定了Treg的抑制表型。我们设计了三个目标检验这一假设：1) 比较功能性 Tregs 与缺陷性 Tregs 的抗原结合参数； 2）根据力的大小确定 Treg 功能参数； 3) 设计 TCR 序列解耦亲和力、键寿命和响应自身抗原的力水平。因此，我们的项目将为脱髓鞘过程中控制 Treg 功能和功能障碍的机制提供新的见解自身免疫性疾病。我们的工作将是第一个研究不同水平的力作为有效的生物标志物 Treg 决定了它们的抑制功效、效力和表型稳定性。