Cellular and Molecular Basis of Gamma/Delta T Cell Antigen Recognition

Gamma/Delta T 细胞抗原识别的细胞和分子基础

基本信息

批准号：
8663991
负责人：
Kaushik Choudhuri
金额：
$ 5.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663991
关键词：
Address Animal Model Antigen Receptors Antigens Bacterial Infections Bacterial Meningitis Binding Biochemical Biological CD8B1 gene Cell physiology Cell surface Cells Characteristics Disease Epithelial Event Genetic Goals Hepatitis delta Antigens Histocompatibility Antigens Human Imaging technology Immune Immunity Immunologic Monitoring In Vitro Infection Infectious Agent Inflammation Inflammatory Interferon Type II Interleukin-17 Invaded Knowledge Lead Ligation Lipids Lymphocyte Malaria Meningitis Malignant Neoplasms Mediating Meningeal Tuberculosis Modality Molecular Monitor Mycobacterium Infections Neutrophil Infiltration Organism Outcome Parasitic infection Pathway interactions Peptides Property Proteins Receptor Signaling Recruitment Activity Role Signal Transduction Signaling Molecule Site Stress Structure Surface T Gamma-Delta Lymphocyte T-Lymphocyte Testing Therapeutic Transgenic Mice Uncertainty Virus Diseases Work adaptive immunity base cytokine design experience functional outcomes imaging modality immune activation immunological synapse immunological synapse formation in vivo killings mucosal site neoplastic neutrophil pathogen perforin preference receptor response spatiotemporal submicron vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): Gamma/delta (gd) T cells are specialized immune cells that are thought to be a first line of defense against major infections. They are known to be activated early during infections such as tuberculosis, malaria, and bacterial meningitis. gd T cells recognize and respond to infectious agents using a receptor (the gd antigen receptor, or gd TCR) on their surface, which binds to parts of infecting organisms (antigens) or other molecules on infected cells that indicate their presence. In addition to recognition of invading organisms by the gd TCR, other 'costimulatory' and 'accessory' surface receptors cooperate to generate biochemical signals to activate the cell. This results in the release of proteins that kill infected cells (eg. perforin), as well as soluble factors (eg. cytokines IFNg and IL-17) that attract other types of immune cells, such as neutrophils and conventional ab T cells, to sites of infection and inflammation. Surprisingly little is known about how the gd TCR, along with associated accessory and costimulatory receptors, work to activate the cell. These molecular interactions, which together form the basis for antigen recognition, is thought to take place at a specialized junction that forms between gd T cells and infected cells known as the immunological synapse, but how it is organized and functions is unclear. It also seems that gd T cells must recognize components of infecting organisms when they are bound to other 'presenting' molecules on the cell surface. However, the identity of these molecules and the strategies used by gd TCRs to recognize them, remain obscure. These uncertainties about how gd T cells recognize and are activated by infections present major impediments to their effective harnessing in treatments and vaccination strategies targeting these diseases. I aim to understand the molecular underpinnings of gd T cell function using advanced in vitro and in vivo imaging technologies, to identify mechanisms of immune activation in these cells that are critical for their role in responding to infections. This work will lead to a more detailed understanding of these medically relevant immune cells, and may contribute to the design of strategies to enhance our immune defenses by boosting gd T cell function.

描述（由申请人提供）：γ/delta（GD）T细胞是专门的免疫细胞，被认为是针对主要感染的第一道防线。已知它们在感染期间早期被激活，例如结核病，疟疾和细菌性脑膜炎。 GD T细胞在其表面上使用受体（GD抗原受体或GD TCR）识别并反应感染剂，该受体（GD抗原受体或GD TCR）与感染生物体（抗原）或其他指示其存在的感染细胞上的其他分子结合。除了识别GD TCR入侵生物外，其他“共刺激”和“附属”表面受体还配合了生化信号以激活细胞。这导致释放杀死受感染细胞的蛋白质（例如穿孔蛋白），以及可溶性因子（例如细胞因子IFNG和IL-17）吸引其他类型的免疫细胞，例如中性粒细胞和常规AB T细胞，以感染和炎症部位。令人惊讶的是，对于GD TCR以及相关的附件和共刺激受体如何激活细胞的知识知之甚少。这些分子相互作用共同构成了抗原识别的基础，被认为是在GD T细胞和被称为免疫突触的感染细胞之间形成的专门连接处发生的，但是如何组织和功能尚不清楚。 GD T细胞似乎还必须识别感染生物的组成部分，当它们与细胞表面的其他“呈现”分子结合时。但是，这些分子的身份以及GD TCR识别它们的策略，保持晦涩难懂。这些关于GD T细胞如何识别和被感染激活的不确定性对其在治疗和针对这些疾病的疫苗接种策略方面的有效利用造成了重大障碍。我的目标是使用先进的体外和体内成像技术了解GD T细胞功能的分子基础，以鉴定这些细胞中免疫激活的机制，这些机制对于它们在反应感染中的作用至关重要。这项工作将导致对这些与医学相关的免疫细胞的更详细的了解，并可能有助于设计通过增强GD T细胞功能来增强我们的免疫防御的策略。