Deciphering the specificity and molecular mechanisms of regulatory T cells using novel approaches

使用新方法破译调节性 T 细胞的特异性和分子机制

• 批准号: 10576791
• 负责人: Billur Akkaya
• 金额: $ 46.73万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-19 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576791
• 关键词: Address; Adult; Affect; Antigen Receptors; Antigen Targeting; Antigen-Presenting Cells; Antigens; Attention; Autoantigens; Autoimmune Diseases; Autoimmunity; Award; Binding; Biological Process; Biological Response Modifier Therapy; Bystander Suppression; Cell Communication; Cell Count; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Chronic; Chronic Disease; Clinical Trials; Clonality; Clone Cells; Complex; Conceptions; Defect; Defense Mechanisms; Dendritic Cells; Development; Discrimination; Disease; Disease Progression; Dose; Epitope spreading; Epitopes; Event; Excision; Flow Cytometry; Future; Genes; Health; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Human; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunosuppression; Immunotherapy; In Vitro; Individual; Infection; Inflammation; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Knowledge; Left; Malignant Neoplasms; Mediating; Methods; Mission; Modality; Molecular; National Institute of Allergy and Infectious Disease; Nature; Organ; Outcome; Outcome Study; Paracrine Communication; Pathologic; Pathway interactions; Patients; Peptides; Population; Precision therapeutics; Prevalence; Regulatory T-Lymphocyte; Reporting; Role; Self Tolerance; Shapes; Signal Transduction; Specificity; Stimulus; Surface Antigens; T cell therapy; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Thymus Gland; Time; Tissues; United States; Visualization; Western Blotting; autoreactive T cell; autoreactivity; combat; effector T cell; experimental study; immunomodulatory strategy; in vivo; man; middle age; mortality; novel; novel strategies; peripheral tolerance; prevent; stem; targeted treatment; therapeutically effective; treatment strategy; two photon microscopy; Address; Adult; Affect; Antigen Receptors; Antigen Targeting; Antigen-Presenting Cells; Antigens; Attention; Autoantigens; Autoimmune Diseases; Autoimmunity; Award; Binding; Biological Process; Biological Response Modifier Therapy; Bystander Suppression; Cell Communication; Cell Count; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Chronic; Chronic Disease; Clinical Trials; Clonality; Clone Cells; Complex; Conceptions; Defect; Defense Mechanisms; Dendritic Cells; Development; Discrimination; Disease; Disease Progression; Dose; Epitope spreading; Epitopes; Event; Excision; Flow Cytometry; Future; Genes; Health; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Human; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunosuppression; Immunotherapy; In Vitro; Individual; Infection; Inflammation; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Knowledge; Left; Malignant Neoplasms; Mediating; Methods; Mission; Modality; Molecular; National Institute of Allergy and Infectious Disease; Nature; Organ; Outcome; Outcome Study; Paracrine Communication; Pathologic; Pathway interactions; Patients; Peptides; Population; Precision therapeutics; Prevalence; Regulatory T-Lymphocyte; Reporting; Role; Self Tolerance; Shapes; Signal Transduction; Specificity; Stimulus; Surface Antigens; T cell therapy; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Thymus Gland; Time; Tissues; United States; Visualization; Western Blotting; autoreactive T cell; autoreactivity; combat; effector T cell; experimental study; immunomodulatory strategy; in vivo; man; middle age; mortality; novel; novel strategies; peripheral tolerance; prevent; stem; targeted treatment; therapeutically effective; treatment strategy; two photon microscopy

Project Summary: Autoimmunity is a leading cause of chronic illness that encompasses more than 80 individual diseases. Due to the rising prevalence of these diseases, autoimmunity associated health problems currently affect over 20 million individuals only in the USA, constituting a health crisis that requires immediate attention. Autoimmune diseases stem from disturbances in the tolerance of immune system against self-tissues. Immune tolerance is achieved in part by the elimination of self-reactive T cells during their development in the thymus. The self-reactive clones that escape thymic elimination are actively silenced in the periphery by a subset of T cells called “regulatory” T (Treg) cells. Because Treg defects result in fatal autoimmunity, increasing Treg number and activity in the body appears to be a desirable strategy to prevent and treat autoimmune diseases. However, we have a major gap in our understanding of how Tregs perform their inhibitory roles at the molecular level and this hinders the development of effective therapeutic strategies. Recently, I demonstrated, for the first time, that Tregs can inhibit effector T cells in an antigen-specific manner. I reported that Treg antigen receptor (TCR) can remove class II major histocompatibility complex bound antigenic peptide (pMHCII) from surface of antigen presenting cell (APC), dendritic cell (DC) in particular, thus deplete the antigenic stimulus that effector T cell needs to receive to get activated. I revealed that this happens during Treg-Dendritic cell (DC) contact, whereby cognate pMHCII laden DC membrane is captured by Treg in an elegant way that does not reduce the presentation of non-cognate pMHCII by the same DC. I hypothesize that this highly specific mechanism can be exploited to effectively reduce pathological presentation of self-antigen by APC as a promising strategy to combat autoimmunity. I will test this hypothesis by taking the following steps: 1) Determining the antigen specificity of Treg suppression and pMHCII removal in human Tregs and visualizing their interactions with DCs that present self-antigens. 2) Characterizing the molecular machinery employed by Tregs to perform pMHCII depletion and dissect the molecular switches that can be targeted to tune Treg activity. 3) Determining the functional significance of antigen capture by Tregs to reveal potential mechanisms whereby Tregs present captured pMHCII complexes to prime naive T cells resulting in the spreading of antigen specific tolerance. By uncovering novel pathways of antigen-specific immune suppression, this New Innovator Award will identify new targets for immune system modulation that can be utilized for the treatment of chronic diseases such as autoimmunity and cancer. Findings from this project will be instrumental in generating future antigen-targeted immunotherapies, thus the objectives of this New Innovator Award serve the strategic mission of the National Institute of Allergy and Infectious Diseases.

项目摘要：自身免疫是慢性疾病的主要原因，包括80多个 个体疾病。由于这些疾病的患病率上升，自身免疫相关的健康问题 目前仅在美国影响超过2000万个人，构成了一场健康危机，需要立即 注意力。自身免疫性疾病源于免疫系统对自我组织的耐受性的干扰。 免疫耐受性部分是由于消除自反应性T细胞在其发展过程中的消除而实现的 胸腺。逃脱胸腺消除的自我反应性克隆在外围被积极沉默 T细胞的子集称为“调节” T（Treg）细胞。因为Treg缺陷导致致命自身免疫性，所以 人体中的Treg数量和活动增加似乎是预防和治疗的理想策略 自身免疫性疾病。但是，我们对Tregs如何执行他们的理解有一个重大差距 在分子水平上的抑制作用，这阻碍了有效的治疗策略的发展。 最近，我首次证明了Treg可以以抗原特异性抑制效应T细胞。 我报道说Treg抗原受体（TCR）可以去除II类主要组织相容性复合物结合 抗原性胡椒（PMHCII）尤其是抗原表面（APC），树突状细胞（DC）的表面，因此 耗尽抗原刺激，效应T细胞需要接收才能被激活。我透露了 发生在Treg Dendritic Cell（DC）接触期间，从而捕获同源PMHCII LADY DC膜 Treg的优雅方式不会减少同一DC的非同名PMHCII的呈现。我 假设可以探索这种高度特定的机制以有效地减少病理表现 APC的自我抗原作为应对自身免疫性的承诺策略。我将通过采用 以下步骤：1）确定人类中Treg抑制和PMHCII去除的抗原特异性 Tregs并可视化他们与具有自我抗原的DC的相互作用。 2）表征分子 Tregs使用的机械执行PMHCII部署并剖析可以是的分子开关 针对Tune Treg活性。 3）确定treg捕获抗原捕获的功能意义 揭示了潜在的机制，从而使Treg捕获了pMHCII复合物至原始的T细胞 导致抗原特异性耐受性的扩散。通过发现抗原特异性的新型途径 免疫抑制，这项新的创新奖将确定免疫系统调制的新目标 可以用来治疗自身免疫和癌症等慢性疾病。从中的发现 项目将有助于产生未来的抗原靶向免疫疗法，因此该目标的目标 新的创新奖颁发了美国国家过敏和传染病研究所的战略使命。