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: 8300595
• 负责人: Kaushik Choudhuri
• 金额: $ 9.36万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300595
• 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; public health relevance; 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 infecte 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. Public Health Relevance: Gamma/delta (gd) T lymphocytes are specialized immune cells that are a first line of defense against major infections and malignancies. Surprisingly little is known about how they function, which hampers their effective exploitation in therapies targeting these diseases. I aim to understand the molecular underpinnings of gd T cell function with the ultimate goal of using this knowledge to enhance our immune defenses by boosting their function.

描述(申请人提供)：伽马/德尔塔(Gd)T细胞是一种特殊的免疫细胞，被认为是抵御重大感染的第一道防线。众所周知，它们是 在结核病、疟疾和细菌性脑膜炎等感染期间早期激活。Gd T细胞通过其表面的受体(gd抗原受体，或gd TCR)识别和响应感染性病原体，该受体与感染生物(抗原)的部分或感染细胞上指示它们存在的其他分子结合。除了通过以下方式识别入侵生物之外 Gdtcr，其他的‘共刺激’和‘辅助’表面受体共同产生生化信号来激活细胞。这会导致杀死感染细胞的蛋白质的释放(例如，穿孔素)，以及可溶性因子(如细胞因子IFNG和IL-17)，吸引其他类型的免疫细胞，如中性粒细胞和常规的ab T细胞，到感染和炎症部位。令人惊讶的是，人们对gdtcr以及相关的辅助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构成了抗原识别的基础，被认为发生在gd T细胞和被称为免疫突触的感染细胞之间的一个特殊连接处，但它是如何组织和功能的尚不清楚。当gd-T细胞与细胞表面的其他“递呈”分子结合时，gd-T细胞似乎必须识别感染生物的成分。然而，这些分子的身份以及gd TCRs识别它们的策略仍然模糊不清。这些关于gd T细胞如何识别和被感染激活的不确定性，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构成了主要障碍。我的目标是利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，以确定这些细胞中免疫激活的机制，这些机制对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。 公共卫生相关性：伽马/德尔塔(Gd)T淋巴细胞是一种特殊的免疫细胞，是抵御重大感染和恶性肿瘤的第一道防线。令人惊讶的是，人们对此知之甚少 关于它们的功能，这阻碍了它们在针对这些疾病的治疗中的有效利用。我的目标是了解gd T细胞功能的分子基础，最终目的是利用这一知识通过增强它们的功能来增强我们的免疫防御。