Differential Roles of TLR2 and TLR4 in Adaptive Immunity

描述（由申请人提供）：肺结核（TB）在美国和全世界都是一个重大的公共卫生问题。最近，耐多药结核病（MDR-TB）已成为一种新的传染病威胁。在缺乏有效抗生素治疗的情况下，有必要开发治疗方法来增强宿主对耐多药结核杆菌的免疫力。针对结核分枝杆菌（Mtb）的保护性免疫是由先天和适应性免疫机制赋予的，结核分枝杆菌是导致肺结核的细菌。结核分枝杆菌的生长最初是由先天免疫细胞（如肺泡巨噬细胞）控制的，这些细胞也是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反应，主要由分泌γ干扰素（IFN）的CD4+ T细胞赋予，是保护性宿主反应所必需的。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蛋白的参与激活了多种先天免疫反应。此外，TLR功能对于树突状细胞的成熟和激活是必需的。树突状细胞对启动适应性免疫反应至关重要，因为它们能够处理细菌抗原并将其呈递给na' ve T细胞。我们最近观察到TLR2和TLR4都参与了宿主对分枝杆菌感染的反应。此外，这些TLR蛋白似乎调节宿主反应的不同方面。TLR2似乎是激活先天免疫应答所必需的，而TLR4似乎调节幼稚抗原特异性T辅助前体（Thp）细胞向产生IFNg的Thl表型的极化。我们的具体目标将确定(1)TLR2-/-小鼠是否由于树突状细胞成熟和/或激活的内在缺陷而无法发育抗原特异性T细胞，以及(2)TLR4-/-小鼠的抗原特异性CD4+ T细胞是否由于Thp细胞向Th1表型的内在缺陷而无法分泌γ IFN。

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.