Differential Roles of TLR2 and TLR4 in Adaptive Immunity

TLR2 和 TLR4 在适应性免疫中的不同作用

• 批准号: 6737540
• 负责人: Matthew J. Fenton
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737540
• 关键词: Mycobacterium tuberculosis; bactericidal immunity; dendrites; enzyme linked immunosorbent assay; flow cytometry; gene targeting; genetically modified animals; helper T lymphocyte; interferon gamma; laboratory mouse; leukocyte activation /transformation; macrophage; polymerase chain reaction; tissue /cell culture; toll like receptor

DESCRIPTION (provided by applicant): Pulmonary tuberculosis (TB) is a significant public health problem both in the United States, and worldwide. More recently, multi-drug resistant TB (MDR-TB) has emerged as a new infectious disease threat. In the absence of effective antibiotic therapy, there is a need to develop therapeutic approaches to augment host immunity against MDR-TB bacilli. Protective immunity against Mycobacterium tuberculosis (Mtb), the bacterium responsible for pulmonary TB, is conferred by both innate and adaptive immune mechanisms. Control of Mtb growth is initially conferred by innate immune cells, such as alveolar macrophages, which also serve as the host cells for this intracellular pathogen. By themselves, these innate immune mechanisms cannot eradicate the infection. Antigen-specific adaptive immune responses, predominantly conferred by gamma interferon (IFN)-secreting CD4+ T cells, are necessary for a protective host response. Toll-like receptor (TLR) proteins are pattern recognition receptors that recognize a variety of mycobacterial products. Engagement of TLR proteins activates variety of innate immune responses. In addition, TLR function is necessary for the maturation and activation of dendritic cells. Dendritic cells are crucial to the initiation of adaptive immune responses because of their ability to process and present bacterial antigens to na'fve T cells. We recently observed that both TLR2 and TLR4 participate in the host responses against mycobacterial infection. Furthermore, these TLR proteins appear to regulate different aspects of the host response. TLR2 appears to be necessary for the activation of innate immune responses, whereas TLR4 appears to regulate the polarization of naive antigen-specific T helper precursor (Thp) cells towards an IFNg- producing Thl phenotype. Our specific aims will determine (1) whether TLR2-/- mice fail to develop antigen-specific T cells because of an intrinsic defect in the maturation and/or activation of dendritic cells, and (2) whether antigen-specific CD4+ T cells from TLR4-/- mice fail to secrete gamma IFN because of an intrinsic defect in commitment of Thp cells to a Th1 phenotype.

描述（由申请人提供）：肺结核（TB）是美国和世界范围内的重大公共卫生问题。最近，耐多药结核病（MDR-TB）已成为一种新的传染病威胁。在缺乏有效的抗生素治疗的情况下，需要开发治疗方法来增强针对MDR-TB杆菌的宿主免疫力。针对结核分枝杆菌（Mtb）（肺结核的病原菌）的保护性免疫由先天性和适应性免疫机制赋予。Mtb生长的控制最初由先天性免疫细胞（例如肺泡巨噬细胞）赋予，所述先天性免疫细胞也充当这种细胞内病原体的宿主细胞。这些先天免疫机制本身不能根除感染。抗原特异性适应性免疫应答主要由分泌γ干扰素（IFN）的CD 4 + T细胞赋予，是保护性宿主应答所必需的。Toll样受体（TLR）蛋白是识别多种分枝杆菌产物的模式识别受体。TLR蛋白的参与激活多种先天免疫应答。此外，TLR功能对于树突状细胞的成熟和活化是必需的。树突状细胞对于适应性免疫应答的启动是至关重要的，因为它们能够加工细菌抗原并将其呈递给幼稚T细胞。我们最近观察到TLR 2和TLR 4都参与了宿主对分枝杆菌感染的应答。此外，这些TLR蛋白似乎调节宿主反应的不同方面。TLR 2似乎是激活先天免疫应答所必需的，而TLR 4似乎调节幼稚抗原特异性T辅助前体（Thp）细胞朝向产生IFNg的Thl表型的极化。我们的具体目标将确定（1）TLR 2-/-小鼠是否由于树突细胞成熟和/或活化的内在缺陷而不能产生抗原特异性T细胞，和（2）来自TLR 4-/-小鼠的抗原特异性CD 4 + T细胞是否由于Thp细胞向Th 1表型定型的内在缺陷而不能分泌γ IFN。