Structural correlates of T cell receptor signaling

T 细胞受体信号传导的结构相关性

• 批准号: 10308085
• 负责人: Kenan Christopher GARCIA
• 金额: $ 50.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308085
• 关键词: Adoptive Cell Transfers; Affinity; Agonist; Amino Acids; Ankylosing spondylitis; Antibodies; Antigens; Autoantigens; Autoimmune; Autoimmunity; Binding; Biological Models; Biology; Blood; Bypass; Cancer Patient; Cells; Chemistry; Clinic; Clinical Trials; Clone Cells; Communicable Diseases; Complex; Development; Disease; Docking; Engineering; Exhibits; Experimental Models; Geometry; HLA-B27 Antigen; Health; Homeostasis; Human; Immune; Immune system; Immunotherapeutic agent; Immunotherapy; Libraries; Ligands; MHC antigen; Malignant Neoplasms; Modeling; Molecular; Mus; Orphan; Pathogenicity; Patients; Peptide/MHC Complex; Peptides; Phase; Physiological; Property; Protein Engineering; Rapid screening; Reagent; Receptor Signaling; Refractory; Regulatory T-Lymphocyte; Role; Signal Transduction; Source; Specificity; Structure; System; T-Cell Receptor; T-Lymphocyte; TCR Activation; Technology; Testing; Tissues; Toxic effect; Ursidae Family; Vaccines; Validation; Yeasts; base; cancer immunotherapy; cell killing; clinical translation; clinically translatable; cross reactivity; improved; insight; novel; novel strategies; preservation; receptor; response; screening; translational impact; tumor

Abstract: The T cell receptor interaction with peptide-MHC is unique in that each receptor has the capacity to engage and differentially respond to functionally distinct ligands. Understanding the molecular basis for these properties is important not only for mechanistic insight but for clinical translation to antigen-specific immunotherapies. In this proposal we focus on the chemistry of the TCR/pMHC interface, its role in the specificity of both the recognition and triggering phases of TCR signal initiation, and the use of this information to advance immunotherapeutic strategies. In the prior term of this proposal, we developed a technology, yeast peptide-MHC display, which enabled us obtain a deep understanding of the extent of TCR specificity and cross-reactivity. We found that TCRs are highly specific for their cognate antigens despite exhibiting cross-reactivity. This property enabled us to recover the known peptide ligands of TCRs through un-biased screening of pMHC libraries. Now, in Aim #1, this finding has opened up many exciting possibilities: principally to use pMHC display technology to query the specificity of TCRs, and to identify peptide ligands for ‘orphan’ TCRs in the natural immune system (e.g. Treg) or from pathogenic systems (e.g. cancer, autoimmunity, infectious disease). In Aim #2 we wish to then then generate high-affinity “TCR mimic” antibodies, using a novel platform approach, that specifically recognize these newly discovered ligands and enables us to track tissue expression and inducing selective killing of cells expressing these antigens. In Aim #3, we show that pMHC library technology is also powerful for understanding the relationship between TCR recognition of pMHC and signaling through the capacity of this approach to generate large panels of peptides that can be characterized with respect to signaling and structure. Using this technology, we made the surprising finding that high-affinity, but non-stimulatory pMHC ligands exist in the natural human immune repertoire. We were able to ‘isolate’ the mechanism of TCR triggering to the formation of “catch bonds” in the TCR/pMHC interface, which can decouple TCR/pMHC binding strength from signaling. In Aim #3 of the current proposal we wish to expand on our studies of non-stimulatory TCRs to better understand the molecular mechanisms of triggering at the TCR/pMHC interface, and test a new idea, ‘catch bond engineering,’ for modifying TCRs to exhibit improved target killing potency in a way that bypasses the dangers of affinity-matured TCRs in adoptive cell therapy. Collectively, this proposal aims to exploit ‘first principles’ of TCR/pMHC binding chemistry along three different fronts that have direct translational impact.

抽象的： T细胞受体与胡椒-MHC的相互作用是独一无二的，因为每个受体都有参与的能力和 对功能上不同的配体的反应不同。了解这些特性的分子基础是 不仅对于机械洞察力，而且对于临床转化为抗原特异性免疫疗法。在这个 提案我们专注于TCR/PMHC接口的化学，其在识别的特异性中的作用 并触发TCR信号计划的阶段，并使用此信息来推动免疫治疗性 策略。在此提案的前学期，我们开发了一种技术，酵母辣椒-MHC显示器， 使我们能够深入了解TCR特异性和交叉反应性的程度。我们发现 TCR对于表现出交叉反应性的同源抗原目的地高度特异。此属性启用了我们 通过对PMHC库的无偏筛选，回收了TCR的已知肽配体。现在，在AIM＃1中， 这一发现打开了许多令人兴奋的可能性：主要是使用PMHC显示技术查询 TCR的特异性，并鉴定自然免疫系统中“孤儿” TCR的肽配体（例如Treg） 或来自致病系统（例如癌症，自身免疫性，传染病）。在AIM＃2中，我们希望那时 使用新型平台方法生成高亲和力的“ TCR模拟”抗体，该抗体专门识别这些抗体 新发现的配体，使我们能够跟踪组织表达并诱导细胞的选择性杀死 表达这些抗原。在AIM＃3中，我们表明PMHC图书馆技术也有助于理解 通过这种方法的能力，TCR识别PMHC的识别与信令之间的关系 产生大量的宠物，可以在信号传导和结构方面表征。使用此 技术，我们令人惊讶地发现，高亲和力，但没有刺激性PMHC配体存在于 天然人类免疫曲目。我们能够“隔离” TCR触发的机制 TCR/PMHC界面中的“捕获键”可以使TCR/PMHC结合强度从信号传导中解脱出来。在 目前的目的＃3我们希望扩展我们对非刺激性TCR的研究，以更好地理解 在TCR/PMHC接口处触发的分子机制，并测试一个新想法，‘Catch Bond 工程学，以修改TCR以绕过危险的方式表现出改善的目标杀死效力 自适应细胞疗法中亲和力成熟的TCR。总的来说，该提议旨在利用 TCR/PMHC结合化学沿三个具有直接翻译影响的不同方面。