Differential Roles of TLR2 and TLR4 in Adaptive Immunity

描述(由申请人提供)：肺结核(TB)在美国和世界范围内都是一个重要的公共卫生问题。最近，耐多药结核病(MDR-TB)已成为一种新的传染病威胁。在缺乏有效的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。对结核分枝杆菌(Mtb)的保护性免疫是由先天免疫机制和获得性免疫机制共同作用的结果。结核分枝杆菌生长的控制最初是由先天免疫细胞，如肺泡巨噬细胞，它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并不能根除感染。抗原特异性获得性免疫反应主要由分泌干扰素的CD4T细胞产生，是保护性宿主反应所必需的。Toll样受体(Toll-like Receptor，TLR)蛋白是一种模式识别受体，识别多种分枝杆菌产物。TLR蛋白的参与激活了多种先天免疫反应。此外，TLR功能是树突状细胞成熟和激活所必需的。树突状细胞是启动获得性免疫反应的关键细胞，因为它们能够处理细菌抗原并将其呈递给原始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应答。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反应所必需的，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。我们的具体目标将决定(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未能产生抗原特异性T细胞，以及(2)TLR4-/-小鼠的抗原特异性CD4T细胞是否由于THP细胞对Th1表型的固有缺陷而未能分泌γ-干扰素。

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.