Recognition of cross-reactive antigens by human CD4+ T cells

人类 CD4 T 细胞对交叉反应抗原的识别

• 批准号: 8700117
• 负责人: Jun Huang
• 金额: $ 9.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700117
• 关键词: Accounting; Address; Adhesions; Advanced Development; Advisory Committees; Affinity; Antigens; Applications Grants; Area; Binding; Biological; Biological Assay; Biomedical Engineering; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Calcium Signaling; Cell Proliferation; Cell membrane; Cells; Communicable Diseases; Complex; Data; Detection; Diagnostic; Dose; Educational workshop; Environment; Epitopes; Faculty; Frequencies; Future; Goals; Hepatitis C; Hour; Human; Image; Imaging Techniques; Immune response; Immunity; Immunologist; Immunology; Immunotherapy; In Situ; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Interdisciplinary Study; Interleukin-2; Investigation; Kinetics; Knowledge; Laboratories; Leadership; Life; Measures; Mechanics; Memory; Mentors; Methodology; Methods; Molecular; Nanotechnology; Occupations; Peptide/MHC Complex; Peptides; Population; Positioning Attribute; Postdoctoral Fellow; Prevention; Process; Production; Publications; Quantum Dots; Regulation; Research; Research Personnel; Resources; Scientist; Secure; Sensitivity and Specificity; Signal Transduction; Specificity; Staining method; Stains; Surface; Synapses; T memory cell; T-Cell Receptor; T-Lymphocyte; Techniques; Technology; Testing; Time; Training; Universities; Vaccination; Viral; base; career; career development; clinical application; cross reactivity; cytokine; fascinate; immune function; immunological synapse formation; improved; infectious disease treatment; insight; memory CD4 T lymphocyte; microorganism; millisecond; novel; novel vaccines; professor; public health relevance; receptor; response; single cell analysis; single molecule; symposium; time use; vaccine development

DESCRIPTION (provided by applicant): I am a bioengineer fascinated by T cell immunology, and I have expertise in single-molecule mechanical analysis, single-molecule imaging, quantum dot nanotechnology, and single-cell signaling and functional assays. My immediate career goal is to secure an independent tenure-track faculty position at a research-intensive university in the coming years, and my long-term goal is to become a leading scientist in the area of TCR recognition and signaling. Stanford University provides a superb training environment to fulfill my career goals. My primary mentor, Professor Mark Davis, is a world-leading molecular immunologist. He has mentored over 50 postdocs and half of them have moved on to tenure-track academic positions at renowned universities. My career training will be conducted under the guidance of Professor Davis as well as an Advisory Committee comprised of six Stanford professors, specifically convened to assist me in becoming an independent principle investigator. Based on my background and career goals, my training will concentrate on experimental techniques, advanced methodologies, faculty job search, multidisciplinary collaborations, laboratory management, grant application and scientific publication. Stanford provides the best possible environment for my career development through world-leading faculty, facilities and resources as well as through a broad coverage of courses, workshops, seminars, conferences and leadership. My proposed research will focus on TCR cross-reactivity. We recently found that H1N1 influenza-specific memory CD4+ cells generated by vaccination cross-react with peptides derived from three common microorganisms of the human microbiota with the fraction of cross-reactive T cells accounting for ~10% of the H1N1-reactive T cells in healthy donors (Su et al., 2013, Immunity). Thus TCR cross-reactivity to environmental antigens could be a major mechanism in eliciting populations of memory T cells for foreign antigens that an individual has not yet encountered. Understanding TCR cross-reactivity is of critical importance in fundamental T cell immunology as well as vaccine development and immunotherapy against infectious diseases. My hypothesis is that the cross-reactivity of the TCR correlates to the binding kinetics of the TCR-pMHC interaction. This is an important question with far-reaching clinical applications, but progress has been limited due to formidable technological challenges since T cell recognition occurs over a wide time-scale ranging from milliseconds to hours and involves dynamic surface molecular interactions and complex cellular signaling and functional regulation. I am proposing to tackle this problem using my state-of- the-art approaches, including single-molecule analysis and single-cell assays as well as the powerful technologies and abundant resources available in our laboratory at Stanford. I will perform a comprehensive investigation on the TCR cross-reactivity at the single-molecule and single-cell level, covering recognition specificity, sensitivity, and kinetics. The knowledge gaine from this study will not only provide indispensable new insights into the immune function of the abundant human memory cells, but also will advance the development of novel vaccines and benefit the prevention and treatment of infectious diseases.

描述（由申请人提供）：我是一名对 T 细胞免疫学着迷的生物工程师，在单分子机械分析、单分子成像、量子点纳米技术以及单细胞信号传导和功能测定方面拥有专业知识。我近期的职业目标是在美国一所研究密集型大学获得独立的终身教职。 未来几年，我的长期目标是成为 TCR 识别和信号传导领域的领先科学家。斯坦福大学为我实现职业目标提供了极好的培训环境。我的主要导师马克·戴维斯教授是世界领先的分子免疫学家。他指导了 50 多名博士后，其中一半已在知名大学担任终身教职。我的职业培训将在戴维斯教授以及由六位斯坦福大学教授组成的咨询委员会的指导下进行，该委员会是专门为帮助我成为一名独立的首席研究员而召集的。根据我的背景和职业目标，我的培训将集中在实验技术、先进方法、教师求职、多学科合作、实验室管理、资助申请和科学出版。斯坦福大学通过世界领先的师资、设施和资源，以及广泛的课程、讲习班、研讨会、会议和领导力，为我的职业发展提供了最好的环境。我提议的研究将集中于 TCR 交叉反应性。我们最近发现，通过疫苗接种产生的 H1N1 流感特异性记忆 CD4+ 细胞与源自人类微生物群的三种常见微生物的肽发生交叉反应，交叉反应性 T 细胞比例约占 H1N1 反应性 T 细胞的 10%。健康的捐赠者（Su et al., 2013, Immunity）。因此，TCR 与环境抗原的交叉反应可能是引发记忆 T 细胞群体针对个体尚未遇到的外来抗原的主要机制。了解 TCR 交叉反应性对于基础 T 细胞免疫学以及针对传染病的疫苗开发和免疫治疗至关重要。我的假设是 TCR 的交叉反应性与 TCR-pMHC 相互作用的结合动力学相关。这是一个具有深远临床应用意义的重要问题，但由于巨大的技术挑战，进展受到限制，因为 T 细胞识别发生在从毫秒到数小时的广泛时间范围内，并且涉及动态表面分子相互作用以及复杂的细胞信号传导和功能。规定。我建议使用最先进的方法来解决这个问题，包括单分子分析和单细胞测定以及我们斯坦福大学实验室强大的技术和丰富的资源。我将在单分子和单细胞水平上对TCR交叉反应性进行全面的研究，涵盖识别特异性、敏感性和动力学。这项研究获得的知识不仅将为丰富的人类记忆细胞的免疫功能提供不可或缺的新见解，还将推动新型疫苗的开发，并有利于传染病的预防和治疗。