Mechanisms of recognition by Mycobacterium tuberculosis-reactive thymocytes

结核分枝杆菌反应性胸腺细胞的识别机制

• 批准号: 8510549
• 负责人: Marielle C. Gold
• 金额: $ 26.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510549
• 关键词: Address; Age-Months; Agonist; Applications Grants; Bacteria; Biological; CD3 Antigens; Cause of Death; Cell Wall; Cells; Cessation of life; Clonal Expansion; Data; Dendritic Cells; Development; Disease; Frequencies; Generations; Goals; Health; Human; Immune; Immune response; Immunity; Incubated; Individual; Infection Control; Interferon Type II; Link; Modeling; Molecular; Morbidity - disease rate; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Receptor Cell; Research; Role; Source; T-Cell Receptor; T-Cell Receptor-Rearrangement Excision DNA Circles; T-Lymphocyte; Testing; Thymus Gland; Time; Tuberculosis; Tuberculosis Vaccines; Umbilical Cord Blood; Vaccines; base; cytokine; design; disorder control; improved; in vivo; mortality; novel; pathogen; peripheral blood; public health relevance; response; thymocyte; tuberculosis immunity

DESCRIPTION (provided by applicant): Project Summary Mycobacterium tuberculosis (Mtb) infects about one third of the population worldwide. An estimated 8 million new cases and 2 million deaths occur annually placing tuberculosis (TB) as a significant health problem. The development of an efficacious vaccine for Mtb will require a better understanding of the Mtb-specific cellular immune response that is critical to control the disease. While the adaptive cellular immune response is essential in the host control of TB, many of the innate immune mechanisms that are required to result in an optimal adaptive cellular immune response to Mtb remain to be characterized. A better understanding of this link is critical in the development of an effective vaccine. We have recently determined that both TB-exposed and unexposed individuals have mucosal associate invariant T cells (MAIT) that are Mtb-reactive. MAIT cells are thought to be innate T cells based on their restricted expression of the semi-invariant Va7.2 T cell receptor (TCR) and their activation via the non-polymorphic HLA-Ib molecule MR1. Although MAIT cells are known to be present at high frequencies in humans the physiological relevance of these cells remains unknown. We hypothesize that MAIT cells may play a role in the control of the bacterium Mycobacterium tuberculosis. We identified a prevalent and high frequency population of abT-cell receptor+ CD3+ CD4- thymocytes in humans that produces IFN-g directly ex vivo in response to Mtb-infected cells. Recently, we determined that a subset of these Mtb-reactive thymocytes expresses the Va7.2 TCR. This application is designed to 1) Determine if MAIT cells represent an Mtb-reactive innate T cell population that can supply an early source of INF-g in the innate control of TB disease as well as providing aid in the acquisition of an optimal adaptive Th1 immune response; 2) Identify the molecular mechanisms by which Va7.2+ Mtb-reactive T cells respond to Mtb-infected cells; 3) Define the Mtb antigen(s) recognized by Va7.2+ Mtb-reactive T cells. These studies may contribute to a more complete understanding of the generation of TB immunity and hence facilitate the development of an improved TB vaccine. PUBLIC HEALTH RELEVANCE: Project Narrative Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality worldwide. Innate cellular mechanisms that contribute to the acquisition of an effective immune response remain to be defined. In our studies of an innate population of T cells from humans we aim to better understand the immune response to TB and hence facilitate the development of an improved TB vaccine.

描述（由申请人提供）： 项目摘要 结核分枝杆菌 (Mtb) 感染全世界约三分之一的人口。据估计，每年出现 800 万新病例和 200 万人死亡，结核病 (TB) 成为一个严重的健康问题。开发有效的结核分枝杆菌疫苗需要更好地了解结核分枝杆菌特异性细胞免疫反应，这对于控制该疾病至关重要。虽然适应性细胞免疫反应对于宿主控制结核病至关重要，但产生针对结核分枝杆菌的最佳适应性细胞免疫反应所需的许多先天免疫机制仍有待表征。更好地理解这种联系对于开发有效的疫苗至关重要。我们最近确定，结核病暴露者和未暴露者都具有 Mtb 反应性粘膜相关不变 T 细胞 (MAIT)。 MAIT 细胞被认为是先天性 T 细胞，因为它们限制性地表达半不变 Va7.2 T 细胞受体 (TCR)，并且通过非多态性 HLA-Ib 分子 MR1 进行激活。尽管已知 MAIT 细胞在人类体内的存在频率很高，但这些细胞的生理相关性仍然未知。我们假设 MAIT 细胞可能在控制结核分枝杆菌中发挥作用。我们鉴定了人类中普遍且高频的 abT 细胞受体 + CD3+ CD4- 胸腺细胞群，它们直接离体产生 IFN-g，以响应 Mtb 感染的细胞。最近，我们确定这些 Mtb 反应性胸腺细胞的一个子集表达 Va7.2 TCR。该应用旨在 1) 确定 MAIT 细胞是否代表 Mtb 反应性先天 T 细胞群，可以在先天控制结核病中提供 INF-g 的早期来源，并为获得最佳适应性 Th1 免疫反应提供帮助； 2）确定Va7.2+ Mtb反应性T细胞对Mtb感染细胞作出反应的分子机制； 3) 定义 Va7.2+ Mtb 反应性 T 细胞识别的 Mtb 抗原。这些研究可能有助于更全面地了解结核病免疫力的产生，从而促进改进结核病疫苗的开发。 公共卫生相关性：项目叙述结核病 (TB) 是全世界传染病发病和死亡的最重要原因之一。有助于获得有效免疫反应的先天细胞机制仍有待确定。在我们对人类先天 T 细胞群的研究中，我们的目标是更好地了解对结核病的免疫反应，从而促进改进结核病疫苗的开发。