Interferon gamma Regulation of CD4 T Cell Responses in Tuberculosis

干扰素 γ 对结核病中 CD4 T 细胞反应的调节

• 批准号: 7666156
• 负责人: KATHERINE C. MACNAMARA
• 金额: $ 5.17万
• 依托单位: NYSDOH/HEALTH RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666156
• 关键词: Address; Aerosols; Antibiotic Resistance; Antigen Presentation Pathway; Antigens; Attenuated; Bacteria; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Cessation of life; Data; Development; Disease; Environment; Exhibits; Gene Expression; Genes; HIV Infections; Histocompatibility; Host Defense; Human; Immune; Immune system; Immunity; Immunocompromised Host; Infection; Infection Control; Interferon Type II; Interleukin-17; Knowledge; Lung; Lymphocyte; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Mediating; Molecular; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Natural Killer Cells; Nitrogen; Oxygen; Patients; Play; Population; Predisposition; Prevention; Production; Public Health; Regulation; Role; Shapes; Signal Transduction; Source; T-Lymphocyte; Testing; Th1 Cells; Tuberculosis; Vaccine Therapy; Vaccines; Wild Type Mouse; cell type; cytokine; human NOS2A protein; immunopathology; in vivo; interferon gamma receptor; interferon gamma receptors; macrophage; mouse model; public health relevance; resistant strain; response

DESCRIPTION (provided by applicant): Tuberculosis is a major public health problem. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), currently infects nearly one third of the human population and causes over 2 million deaths annually. For reasons that are not yet fully understood, the immune system fails to completely clear the infection, which persists in macrophages. The broad objective of this proposal is to elucidate mechanisms regulating immunity during tuberculosis. Control of Mtb infection is attributed to T helper type 1 CD4 T cells which secrete interferon gamma (IFNg). IFNg activates macrophages inducing the production of reactive nitrogen and oxygen intermediates which, in turn, limit bacterial replication and dissemination. IFNg has regulatory effects on many other cell types as well. While CD4 T cells and IFNg are both abundant in the lungs during tuberculosis, we currently do not know if and how IFNg regulates CD4 T cell responses during this infection. Using a well-established mouse model of tuberculosis we will test the hypothesis that IFNg acts directly on CD4 T cells to regulate their differentiation, function and turnover during Mtb infection. We will compare Mtb-specific CD4 T cells that do or do not express a functional IFNg receptor. This approach will allow us to address the direct effects of IFNg on CD4 T cells in an otherwise normal host environment (ie: all other cell types express a functional IFNg receptor). In Aim 1 we will analyze expansion and differentiation of wild type and IFNg receptor-deficient Mtb-specific CD4 T cells in the lungs and relevant lymphoid tissues of Mtb infected mice. Aim 2 will address whether IFNg promotes contraction and/or turnover of CD4 T cells during Mtb infection. In Aim 3 we will address the direct effects of IFNg on CD4 T cells at the molecular level. PUBLIC HEALTH RELEVANCE: The emergence of antibiotic-resistant strains of Mtb, the lack of an effective vaccine and the growing population of immunosuppressed patients (largely due to HIV-infection) contribute to the tuberculosis crisis. It is well-established that IFNg is an essential cytokine that controls Mtb infection, and that CD4 T cells are critical for secreting IFNg. However, our current knowledge of how IFNg contributes to CD4 T cell function is inadequate. Thus, an understanding of the role of IFNg in shaping CD4 T cell differentiation and function is critical for a complete picture of how protective CD4 T cell immunity is established and maintained during Mtb infection.

描述（由申请人提供）：结核病是一个主要的公共卫生问题。结核病的病原体结核分枝杆菌 (Mtb) 目前感染近三分之一的人口，每年导致超过 200 万人死亡。由于尚不完全清楚的原因，免疫系统无法完全清除巨噬细胞中持续存在的感染。该提案的主要目标是阐明结核病期间免疫调节机制。 Mtb 感染的控制归因于分泌干扰素 γ (IFNg) 的 1 型辅助 T CD4 T 细胞。 IFNg 激活巨噬细胞，诱导产生活性氮和氧中间体，从而限制细菌复制和传播。 IFNg 对许多其他细胞类型也有调节作用。虽然结核病期间肺部中 CD4 T 细胞和 IFNg 均大量存在，但我们目前尚不清楚 IFNg 是否以及如何在这种感染期间调节 CD4 T 细胞反应。我们将使用成熟的结核病小鼠模型来检验以下假设：IFNg 直接作用于 CD4 T 细胞，以调节 Mtb 感染期间的分化、功能和周转。我们将比较表达或不表达功能性 IFNg 受体的 Mtb 特异性 CD4 T 细胞。这种方法将使我们能够在正常的宿主环境中解决 IFNg 对 CD4 T 细胞的直接影响（即：所有其他细胞类型都表达功能性 IFNg 受体）。在目标 1 中，我们将分析 Mtb 感染小鼠肺部和相关淋巴组织中野生型和 IFNg 受体缺陷型 Mtb 特异性 CD4 T 细胞的扩增和分化。目标 2 将解决 IFNg 是否促进 Mtb 感染期间 CD4 T 细胞的收缩和/或更新。在目标 3 中，我们将在分子水平上探讨 IFNg 对 CD4 T 细胞的直接影响。 公共卫生相关性：耐抗生素菌株的出现、有效疫苗的缺乏以及免疫抑制患者数量的不断增加（主要是由于艾滋病毒感染）导致了结核病危机。众所周知，IFNg 是控制 Mtb 感染的重要细胞因子，而 CD4 T 细胞对于分泌 IFNg 至关重要。然而，我们目前对 IFNg 如何促进 CD4 T 细胞功能的了解还不够。因此，了解 IFNg 在塑造 CD4 T 细胞分化和功能中的作用对于全面了解 Mtb 感染期间如何建立和维持保护性 CD4 T 细胞免疫至关重要。