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，涵盖 80 多种慢性疾病 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。 目前仅在美国就有超过 2000 万人受到影响，构成了一场健康危机，需要立即采取行动 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 细胞在其发育过程中实现的。 逃避胸腺消除的自我反应克隆在周围被主动沉默。 T 细胞的子集称为“调节性”T (Treg) 细胞，因为 Treg 缺陷会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的理想策略 然而，我们对 Tregs 如何发挥作用的理解存在重大差距。 在分子水平上发挥抑制作用，这阻碍了有效治疗策略的发展。 最近，我首次证明Tregs可以以抗原特异性方式抑制效应T细胞。 我报道Treg抗原受体（TCR）可以去除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 细胞激活所需的抗原刺激。 发生在 Treg 与树突状细胞 (DC) 接触期间，从而捕获同源 pMHCII 负载的 DC 膜 Treg 以一种优雅的方式，不会减少同一 DC I 的非同源 pMHCII 的呈现。 追求可以利用这种高度特异性的机制来有效减少病理表现 通过 APC 检测自身抗原作为对抗自身免疫的一种有前途的策略，我将通过采取以下方法来检验这一假设。 步骤如下： 1) 确定人体内 Treg 抑制和 pMHCII 去除的抗原特异性 Tregs 并可视化它们与呈递自身抗原的 DC 的相互作用 2) 表征分子。 Tregs 使用的机器来执行 pMHCII 消耗并剖析分子开关，这些分子开关可以 3) 确定 Treg 捕获抗原的功能意义。 揭示 Tregs 将捕获的 pMHCII 复合物呈递给初始 T 细胞的潜在机制 通过揭示抗原特异性的新途径，导致抗原特异性耐受的传播。 免疫抑制，新创新奖将确定免疫系统调节的新目标 可用于治疗自身免疫和癌症等慢性疾病。 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 新创新者奖服务于国家过敏和传染病研究所的战略使命。