Recognition of Mtb-infected Cells by CD8+ T Lymphocytes

描述（由申请人提供）：结核病仍然是全世界一个重要的临床问题。结核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依赖于细胞免疫系统的协调反应。由于CD8+ T细胞识别并破坏被细胞内病原体感染的靶细胞，CD8+ T细胞反应可能对结核分枝杆菌的遏制和感染细胞的消除很重要。人类细胞毒性T细胞的鉴定和表征可能对了解结核病免疫至关重要，因此可能需要开发有效的疫苗和改进的治疗策略。在之前的工作中，我们已经证明经典和非经典限制性Mtb特异性反应都存在于Mtb感染者中，已经证明CD8+ T细胞优先识别严重感染的DC，已经证明非经典限制性反应占总体反应的很大一部分，并且已经证明非经典主要组织相容性分子HLA-E可以呈现Mtb衍生抗原。这项工作代表了HLA-lb分子HLA-E在细胞内病原体识别中的首次描述。因此，这种持续应用的目标是进一步我们对这种抗原识别系统的理解。对这一途径的进一步了解对理解宿主对Mtb的反应具有重要意义，并可能改进疫苗设计。因此，本研究计划的重点是确定人类CD8+ T细胞识别结核分枝杆菌感染细胞的机制。

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