Recognition of Mtb-infected Cells by CD8+ T Lymphocytes

CD8 T 淋巴细胞对 Mtb 感染细胞的识别

基本信息

批准号：
8112146
负责人：
DAVID M. LEWINSOHN
金额：
$ 25.53万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-02 至 2011-08-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8112146
关键词：
Antigen Presentation Pathway Antigen-Presenting Cells Antigens Binding Biological Assay Brefeldin A CD8-Positive T-Lymphocytes CD8B1 gene Cell Fractionation Cells Child Clinical Confocal Microscopy Containment Cross Presentation Cytotoxic T-Lymphocytes Data Development Disease Effector Cell Electron Microscopy Elements Frequencies Funding Genetic Goals Golgi Apparatus HLA-E antigen Heat shock proteins Histocompatibility Human Immune response Immune system Individual Infection Location Mass Spectrum Analysis Memory Modification Molecular Mycobacterium tuberculosis Organelles Pathway interactions Pattern Peptide/MHC Complex Persons Phagosomes Post-Translational Protein Processing Process Proteins Reagent Recording of previous events Research Personnel Research Proposals Site Specificity System T cell response T-Cell Receptor T-Cell Receptor-Rearrangement Excision DNA Circles T-Lymphocyte Testing Therapeutic Thymus Gland TimeLine Tuberculosis Vaccine Design Vaccines Work alpha-beta T-Cell Receptor antigen processing base improved inhibitor/antagonist macrophage mutant pathogen programs response thymocyte trafficking tuberculosis immunity

项目摘要

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

描述（由申请人提供）：结核病在全世界仍然是一个重要的临床问题。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。由于 CD8+ T 细胞识别并破坏被细胞内病原体感染的靶细胞，因此 CD8+ T 细胞反应对于遏制 Mtb 和消除感染细胞可能很重要。人类细胞毒性 T 细胞的鉴定和表征对于了解结核病免疫至关重要，因此可能是开发有效疫苗和改进治疗策略所必需的。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感染 Mtb 的人中，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包括总体反应的重要部分，并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使用HLA-1b分子HLA-E来识别细胞内病原体。因此，这种持续应用的目标是进一步加深我们对这种抗原识别系统的理解。加深对该途径的了解对于了解宿主对 Mtb 的反应以及可能改进疫苗设计具有重要意义。因此，本研究计划的重点是确定人类 CD8+ T 细胞识别 Mtb 感染细胞的机制。目标 1：确定 HLA-E 限制性 T 细胞反应与结核病状态的关系。目标 2：确定 Mtb 吞噬体是否是一种有效的抗原加工细胞器目标 3：表征 Mtb 反应性 αβ TCR 表达胸腺细胞