Recognition of Mtb-infected Cells by CD8+ T Lymphocytes

描述（由申请人提供）：结核病仍然是世界各地的一个重要临床问题。结核病的病原体，结核分枝杆菌（Mtb），是一种兼性细胞内病原体，主要存在于巨噬细胞中。对结核病的保护性免疫取决于细胞免疫系统的协调反应。因为CD 8 + T细胞识别并破坏被细胞内病原体感染的靶细胞，所以CD 8 + T细胞应答对于遏制Mtb和消除感染的细胞可能是重要的。人细胞毒性T细胞的鉴定和表征对于理解结核病的免疫力可能是必不可少的，因此可能需要开发有效的疫苗和改进的治疗策略。在先前的工作中，我们已经证明了经典和非经典限制性的Mtb特异性应答都存在于感染Mtb的人中，已经证明了CD 8 + T细胞优先识别严重感染的DC，已经证明了非经典限制性应答包括总体应答的显著部分，并且已经证明非经典的主要组织相容性分子HLA-E可以呈递Mtb衍生的抗原。这项工作代表了HLA-Ib分子HLA-E在识别细胞内病原体中的用途的首次描述。因此，本持续申请的目标是进一步了解这种抗原识别系统。对这一途径的进一步了解对于理解宿主对结核分枝杆菌的反应具有重要意义，并可能对改进疫苗设计具有重要意义。因此，这项研究计划的重点是确定人类CD 8 + T细胞识别Mtb感染细胞的机制。 目的1：确定HLA-E限制性T细胞应答与结核病病情的关系。 目的2：确定结核分枝杆菌吞噬体是否是一个有能力的抗原加工细胞器 目的3：表征表达Mtb反应性α β TCR的胸腺细胞

DESCRIPTION (provided by applicant): Tuberculosis remains an important clinical problem throughout the world. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), is a facultative intracellular pathogen, residing primarily in macrophages. Protective immunity to tuberculosis depends upon the coordinated response of the cellular immune system. Because CD8+ T cells recognize and destroy target cells infected with intracellular pathogens, the CD8+ T cell response may be important for containment of Mtb and elimination of infected cells. Identification and characterization of human cytotoxic T cells may be essential for the understanding of immunity to tuberculosis, and hence may be required for the development of efficacious vaccines and improved therapeutic strategies. In prior work, we have demonstrated that both classically and non-classically restricted, Mtb-specific responses are present in persons infected with Mtb, have demonstrated that CD8+ T cell preferentially recognize heavily infected DC, have demonstrated that non-classically restricted responses comprise a significant fraction of the overall response, and have demonstrated that the non-classical major histocompatibility molecule HLA-E can present Mtb-derived antigen. This work represented the first description of the use of the HLA-lb molecule HLA-E in the recognition of an intracellular pathogen. As a result, the goal of this continuing application is to further our understanding of this antigen recognition system. An increased understanding of this pathway has important implications for understanding the host-response to Mtb, and possibly for improved vaccine design. Thus, this research proposal is focused on defining the mechanisms by which human CD8+ T cells recognize Mtb infected cells. AIM 1: Determine the relationship of HLA-E restricted T cell responses with TB disease status. AIM 2: Establish whether or not the Mtb-phagosome is a competent antigen processing organelle AIM 3: Characterize Mtb-reactive alpha beta TCR expressing thymocytes