Recognition of Mtb-infected Cells by CD8+ T Lymphocytes

描述(申请人提供)：结核病仍然是世界各地的一个重要的临床问题。结核分枝杆菌(Mtb)是一种兼性的细胞内病原体，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CD8T细胞识别和破坏感染了细胞内病原体的靶细胞，CD8T细胞反应对于控制结核分枝杆菌和清除感染细胞可能是重要的。鉴定和鉴定人类细胞毒性T细胞可能是了解结核病免疫的关键，因此可能需要开发有效的疫苗和改进的治疗策略。在以前的工作中，我们已经证明了Mtb感染者存在经典和非经典限制性的Mtb特异性反应，已经证明CD8T细胞优先识别重度感染的DC，已经证明非经典限制性反应在整体反应中占很大比例，并且已经证明非经典主要组织相容性分子HLA-E可以呈递Mtb衍生的抗原。这项工作首次描述了人类白细胞抗原1b分子人类白细胞抗原E在细胞内病原体识别中的应用。因此，这种持续应用的目的是加深我们对这一抗原识别系统的了解。对这一途径的进一步了解对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，本研究计划致力于确定人类CD8T细胞识别结核分枝杆菌感染细胞的机制。 目的1：探讨人类白细胞抗原E限制性T细胞反应与结核病病情的关系。 目的2：确定mtb吞噬小体是否是一个合格的抗原处理细胞器 目的3：鉴定表达结核分枝杆菌反应性α-βTCR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