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

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多种 个别疾病。由于这些疾病的患病率不断上升，自身免疫相关的健康问题 目前仅在美国就影响了2000多万人，构成了一场需要立即采取行动的健康危机。 关注自身免疫性疾病源于免疫系统对自身组织的耐受性紊乱。 免疫耐受部分是通过消除自身反应性T细胞来实现的， 胸腺逃避胸腺消除的自身反应性克隆在外周被一种 T细胞亚群称为“调节性”T（Treg）细胞。因为Treg缺陷导致致命的自身免疫， 增加体内Treg数量和活性似乎是预防和治疗糖尿病的理想策略。 自身免疫性疾病然而，我们在理解Tandem如何执行其功能方面存在重大差距。 在分子水平的抑制作用，这阻碍了有效的治疗策略的发展。 最近，我第一次证明了TcR可以以抗原特异性方式抑制效应T细胞。 我报道了Treg抗原受体（TCR）可清除II类主要组织相容性复合物结合 来自抗原呈递细胞（APC），特别是树突状细胞（DC）表面的抗原肽（pMHCII），因此 耗尽效应T细胞需要接收以被激活的抗原刺激。我透露， 在Treg-树突细胞（DC）接触期间发生，由此捕获载有同源pMHCII的DC膜 通过Treg以不减少相同DC对非同源pMHCII的呈递的优雅方式表达。我 假设这种高度特异性机制可以有效地减少病理表现 自身抗原的APC作为一个有前途的战略，以打击自身免疫。我将测试这个假设， 1）确定人T细胞中Treg抑制和pMHCII去除的抗原特异性 Tumbling和可视化它们与呈递自身抗原的DC的相互作用。2)表征分子 机器采用的THERM进行pMHCII耗尽和解剖分子开关，可以 调节调节性T细胞活性3)确定THBE捕获抗原的功能意义， 揭示了潜在的机制，借此TcR将捕获的pMHCII复合物呈递给初始T细胞 导致抗原特异性耐受性的扩散。通过发现新的抗原特异性 免疫抑制，这个新的创新者奖将确定免疫系统调节的新目标 其可用于治疗慢性疾病如自身免疫和癌症。时发现的问题 该项目将有助于产生未来的抗原靶向免疫疗法，因此，该项目的目标是 新创新奖服务于国家过敏和传染病研究所的战略使命。