Interferon gamma Regulation of CD4 T Cell Responses in Tuberculosis

描述(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)目前感染了近三分之一的人口，每年造成200多万人死亡。由于尚未完全了解的原因，免疫系统未能完全清除感染，感染持续存在于巨噬细胞中。这项建议的广泛目标是阐明结核病期间免疫调节的机制。结核分枝杆菌感染的控制归因于T辅助1型CD4T细胞分泌干扰素γ(IFNG)。IFNG激活巨噬细胞，诱导产生活性氮和氧中间体，进而限制细菌的复制和传播。IFNG对许多其他类型的细胞也有调节作用。虽然在肺结核期间，肺脏中CD4T细胞和IFNG都很丰富，但我们目前还不知道IFNG在这种感染过程中是否以及如何调节CD4T细胞的反应。利用一种成熟的小鼠结核病模型，我们将检验这一假设，即IFNG直接作用于CD4T细胞，在结核分枝杆菌感染期间调节它们的分化、功能和周转。我们将比较结核分枝杆菌特异性CD4T细胞表达或不表达功能性IFNG受体。这种方法将使我们能够在其他正常的宿主环境中解决IFNG对CD4T细胞的直接影响(即：所有其他类型的细胞都表达功能正常的IFNG受体)。在目标1中，我们将分析结核分枝杆菌感染小鼠肺和相关淋巴组织中野生型和IFNG受体缺陷的Mtb特异性CD4T细胞的扩增和分化。目标2将讨论在结核分枝杆菌感染期间，IFNG是否促进CD4T细胞的收缩和/或周转。在目标3中，我们将在分子水平上解决干扰素对CD4T细胞的直接影响。 与公共卫生的相关性：结核分枝杆菌抗药性菌株的出现、缺乏有效的疫苗以及免疫抑制患者(主要是由于艾滋病毒感染)人数的增加，都是造成结核病危机的原因。众所周知，IFNG是控制结核分枝杆菌感染的重要细胞因子，而CD4T细胞是分泌IFNG的关键。然而，我们目前对IFNG如何促进CD4T细胞功能的了解还不够充分。因此，了解IFNG在塑造CD4T细胞分化和功能中的作用，对于全面了解结核分枝杆菌感染期间保护性CD4T细胞免疫是如何建立和维持的至关重要。

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.