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，我在单分子机械分析，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具有专业知识。我近期的职业目标是在美国的一所研究型大学获得一个独立的终身教职。 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。斯坦福大学提供了一个极好的培训环境来实现我的职业目标。我的主要导师Mark Davis教授是世界领先的分子免疫学家。他已经指导了50多名博士后，其中一半已经在知名大学获得了终身教职。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，专门召集会议以帮助我成为一名独立的主要调查员。根据我的背景和职业目标，我的培训将集中在实验技术，先进的方法，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。我建议的研究将集中在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CD 4+细胞与源自人类微生物群的三种常见微生物的肽交叉反应，其中交叉反应性T细胞的分数占健康供体中H1N1反应性T细胞的~10%（Su et al.，2013，Immunity）。因此，TCR对环境抗原的交叉反应性可能是引发记忆T细胞群体对个体尚未遇到的外来抗原的主要机制。了解TCR交叉反应性在基础T细胞免疫学以及针对感染性疾病的疫苗开发和免疫治疗中至关重要。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。这是一个重要的问题，具有深远的临床应用，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，涉及动态表面分子相互作用和复杂的细胞信号传导和功能调节。我建议使用我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的强大技术和丰富资源。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，包括识别特异性，灵敏度和动力学。这项研究所获得的知识不仅将为人类丰富的记忆细胞的免疫功能提供不可或缺的新见解，而且将促进新型疫苗的开发，并有利于预防和治疗传染病。