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

• 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
• 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

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/δ（gd）T细胞是特化的免疫细胞，被认为是对抗主要感染的第一道防线。已知它们在结核病、疟疾和细菌性脑膜炎等感染的早期被激活。gd T细胞使用其表面上的受体（gd抗原受体或gd TCR）识别并响应感染因子，该受体结合感染生物体的部分（抗原）或感染细胞上指示其存在的其他分子。除了通过gd TCR识别入侵的生物体之外，其他“共刺激”和“辅助”表面受体合作产生生物化学信号以激活细胞。这导致蛋白质的释放，杀死感染的细胞（如。穿孔素），以及可溶性因子（例如，细胞因子IFNg和IL-17），其吸引其他类型的免疫细胞，如嗜中性粒细胞和常规ab T细胞至感染和炎症部位。令人惊讶的是，人们对gd TCR沿着相关的辅助受体和共刺激受体如何激活细胞知之甚少。这些分子相互作用共同形成抗原识别的基础，被认为发生在gd T细胞和感染细胞之间形成的称为免疫突触的特化连接处，但它是如何组织和功能尚不清楚。似乎gd T细胞必须识别感染生物体的成分，当它们与细胞表面的其他“呈递”分子结合时。然而，这些分子的身份和gd TCR识别它们的策略仍然不清楚。关于gd T细胞如何识别并被感染激活的这些不确定性，对它们在针对这些疾病的治疗和疫苗接种策略中的有效利用提出了主要障碍。我的目标是了解gd T细胞功能的分子基础，使用先进的体外和体内成像技术，以确定这些细胞中的免疫激活机制，这些机制对于它们在应对感染中的作用至关重要。这项工作将导致对这些医学相关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。