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）：我是一个对T细胞免疫学迷住的生物工程师，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性测定方面具有专业知识。我的直接职业目标是在一所研究密集型大学中确保独立的终身教师职位 未来几年，我的长期目标是成为TCR识别和信号传导领域的主要科学家。斯坦福大学提供了出色的培训环境，以实现我的职业目标。我的主要导师马克·戴维斯（Mark Davis）教授是一位世界领先的分子免疫学家。他指导了50多个博士后，其中一半已经晋升为著名大学的终身学术职位。我的职业培训将在戴维斯教授的指导下以及由六名斯坦福大学教授组成的咨询委员会的指导下进行，特别是为了帮助我成为一名独立的原则调查员。基于我的背景和职业目标，我的培训将集中于实验技术，高级方法论，教职员工搜索，多学科合作，实验室管理，赠款应用和科学出版物。斯坦福大学通过世界领先的教师，设施和资源以及广泛的课程，讲习班，研讨会，会议和领导才能为我的职业发展提供最佳的环境。我提出的研究将集中于TCR交叉反应性。最近，我们发现，由疫苗接种的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衍生的肽产生，而交叉反应T细胞的比例约为健康供体中H1N1反应性T细胞的10％（SU et al。因此，TCR对环境抗原的交叉反应可能是引发个人尚未遇到的外国抗原的记忆T细胞种群的主要机制。了解TCR交叉反应性在基本T细胞免疫学以及疫苗发育和针对传染病的免疫疗法中至关重要。我的假设是，TCR的交叉反应与TCR-PMHC相互作用的结合动力学相关。对于深远的临床应用，这是一个重要的问题，但是由于巨大的技术挑战，由于T细胞识别的范围从毫秒到小时，因此进步受到了限制，并且涉及动态的表面分子相互作用以及复杂的细胞信号传导和功能调节。我建议使用我的AR​​T方法解决此问题，包括单分子分析和单细胞测定法，以及我们在斯坦福大学实验室中提供的强大技术和丰富的资源。我将对单分子和单细胞水平的TCR交叉反应性进行全面研究，涵盖识别特异性，灵敏度和动力学。这项研究的知识获得不仅将为丰富的人类记忆细胞的免疫功能提供必不可少的新见解，而且还将推动新型疫苗的开发，并使预防和治疗传染病。