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

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

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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/摘要全世界有数百万人被诊断出患有自身免疫性疾病，例如多发性硬化症（MS）。 MS的标志是进步的脱髓鞘，这是由不适当的免疫反应驱动的中枢神经系统中的细胞。 MS的主要风险因素和实验性自身免疫性除许多其他自身免疫性疾病（I型糖尿病）外，脑脊髓炎（EAE）动物模型类风湿关节炎等是特定的MHC II类分子。由于MHC II类呈肽抗原至 CD4+ T常规（TCONV）和调节性T细胞（Tregs），T细胞受体之间的相互作用（TCR）和自肽：MHC（PMHC）在自身免疫性疾病进展中起关键作用。至关重要 Treg的目的是以抗原特定方式抑制对自我的免疫反应。 Tregs认识抗原（例如髓磷脂）通过其TCR，但基本措施和TCR的潜在机制与PMHC的相互作用尚不清楚。因此，对抗原特异性反应性的透彻理解 Tregs以及是否可以利用这种活动具有巨大的治疗潜力。在这里，我们将剖析使用敏感技术来测量TCR和髓磷脂抗原之间的相互作用，以测量 TCR结合，例如亲和力和债券寿命。值得注意的是，Tregs将力施加到TCR和TCR之间的键 PMHC，最终由蛋白质相互作用多长时间的变化所反映。据说Treg TCR 信号的强度增强了，从机械上讲，这个概念的定义很差。我们发现了这一点与TCONV细胞相比，抑制性Treg对PMHC键施加更多的力。此外，髓磷脂特异性tregs 那无法抑制较低的力量。因此，我们假设在抗原识别期间增加的力量决定了Treg抑制表型。我们设计了三个目标检验将：1）比较功能性和特雷格的抗原结合参数； 2）确定依赖力大小的Treg功能参数； 3）工程师TCR序列解脱亲和力，粘结寿命和对自我抗原的力量水平。因此，我们的项目将提供有关脱髓鞘期间控制Treg功能和功能障碍的机制的新见解自身免疫性疾病。我们的工作将是第一个调查各种力量作为有力的生物标志物的工作 Treg决定了它们的抑制功效，效力和表型稳定性。