Recognition of Mtb-Infected Cells by Non-Classically Restricted CD8+ T Cells

非经典限制性 CD8 T 细胞对 Mtb 感染细胞的识别

• 批准号: 10554259
• 负责人: DAVID M. LEWINSOHN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554259
• 关键词: Accounting; Anabolism; Antigens; CD8-Positive T-Lymphocytes; Categories; Cell surface; Cells; Cessation of life; Clinical; Collaborations; Communicable Diseases; Data; Development; Diagnostic; Endosomes; Environment; Exposure to; Extended Family; Family; Funding; Grant; Household; Human; Immune response; Immune system; Infection; Intestines; Laboratories; Learning; Ligands; Location; Lung; Macrophage; Memory; Molecular; Molecular Chaperones; Morbidity - disease rate; Mucous Membrane; Mycobacterium tuberculosis; Organism; Outcome; Peptides; Play; Population; Predisposition; Prevalence; Process; Program Reviews; Proteins; RNA Splicing; Research Proposals; Resistance to infection; Riboflavin; Role; Sampling; T-Lymphocyte; Thymus Gland; Tissues; Tuberculosis; Umbilical Cord Blood; Universities; Vaccines; Variant; Vesicle; Vitamin B Complex; Washington; Work; clinically relevant; direct application; improved; microbial; mortality; mycobacterial; pathogen; programs; response; small molecule; trafficking; tuberculosis immunity; uptake

Project Summary Tuberculosis (TB) is a leading cause of infectious disease mortality worldwide, accounting for 10.4 million new cases and 1.3 million deaths annually. An understanding of the immune response to Mtb is of central importance in the development of improved vaccines. In this regard our laboratory, under the auspices of the VA Merit Program, has defined Mucosal Associated Invariant T (MAIT) cells as a class of cells that are restricted by the highly conserved MR1 molecule, recognize Mtb-infected cells, have effector capacity in the thymus and cord blood, yet display evidence for memory following exposure to Mtb, and are enriched in the lungs. MAIT cells are found in tissues such as the lung and intestine. Because MAIT cells recognize small molecules, such as metabolites of riboflavin, we postulate that the cell surface expression of MR1 is tightly regulated to avoid activation of these cells in the absence of intracellular infection. Indeed, with the support of the VA Merit Program, we have found that MR1 is both located in an endosome, requires a ligand for translocation to the cell surface, and is dependent on vesicular trafficking for the presentation of Mtb-derived antigens to MR1T cells. Furthermore, we find that the mechanisms underlying presentation of Mtb-derived antigens can be distinguished from antigens that are exogenously delivered, suggesting that there are specialized mechanisms for sampling the intracellular environment. Therefore, in this application we will focus on defining the molecular mechanisms that allow for the appropriate presentation of intracellular infection, with a focus on Mtb. We will 1) Define the molecular chaperones required for the presentation of microbials ligands, and 2) Define the role of MR1 SNPs and splice variants in controlling the recognition of the Mtb infected cell, and will evaluate these variants in clinically relevant outcomes following exposure to Mtb. This project contains two Aims: AIM 1: Define the molecular chaperones necessary for the presentation of Mtb-derived ligands 1a. Determine the molecular chaperones associated with MR1. 1b. Determine the role of riboflavin transporters in the uptake or trafficking of MR1 ligands. AIM 2: Define the role of MR1 SNPs and splice variants in human susceptibility to TB 2a. Determine the relationship of MR1 SNPs and splice variants and clinical outcomes associated with exposure to Mtb. 2b. Determine the functional significance of MR1 SNPs. 2c. Determine the relationship of MR1 splice variant expression and the capacity of cells to present MR1 ligands to MR1T cells.

项目概要 结核病 (TB) 是全球传染病死亡的主要原因，造成 1,040 万人死亡 每年有 130 万人感染和死亡。了解 Mtb 的免疫反应至关重要 开发改良疫苗。在这方面，我们的实验室在 VA Merit 的支持下 计划将粘膜相关不变 T (MAIT) 细胞定义为一类受 高度保守的 MR1 分子，识别 Mtb 感染的细胞，在胸腺和脊髓中具有效应能力 血液中存在，但在接触结核分枝杆菌后显示出记忆的证据，并且在肺部富集。 MAIT 细胞存在于肺和肠等组织中。因为MAIT细胞识别小分子， 例如核黄素的代谢物，我们假设 MR1 的细胞表面表达受到严格调节 避免在没有细胞内感染的情况下激活这些细胞。事实上，在 VA Merit 的支持下 程序中，我们发现MR1均位于核内体中，需要配体才能转位到细胞中 表面，并且依赖于囊泡运输将 Mtb 衍生的抗原呈递给 MR1T 细胞。 此外，我们发现 Mtb 衍生抗原呈递的机制可以区分 来自外源递送的抗原，表明存在专门的采样机制 细胞内环境。 因此，在本应用中，我们将重点关注定义允许适当的分子机制 介绍细胞内感染，重点是结核分枝杆菌。我们将 1) 定义所需的分子伴侣 用于微生物配体的呈现，以及 2) 定义 MR1 SNP 和剪接变体在控制中的作用 识别 Mtb 感染细胞，并将在以下临床相关结果中评估这些变异 接触 Mtb。 该项目包含两个目标： 目标 1：定义 Mtb 衍生配体呈递所需的分子伴侣 1a.确定与 MR1 相关的分子伴侣。 1b.确定核黄素转运蛋白在 MR1 配体的摄取或运输中的作用。 目标 2：定义 MR1 SNP 和剪接变体在人类结核病易感性中的作用 2a.确定 MR1 SNP 和剪接变体以及相关临床结果的关系 接触 Mtb。 2b.确定 MR1 SNP 的功能意义。 2c.确定 MR1 剪接变体表达与细胞呈递 MR1 能力的关系 MR1T 细胞的配体。