Interferon gamma Regulation of CD4 T Cell Responses in Tuberculosis

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，并且每年导致超过200万人死亡。由于尚未完全了解的原因，免疫系统无法完全清除感染，感染在巨噬细胞中持续存在。这项建议的主要目的是阐明结核病期间免疫调节的机制。Mtb感染的控制归因于分泌干扰素γ（IFNg）的T辅助1型CD 4 T细胞。IFNg激活巨噬细胞，诱导活性氮和氧中间体的产生，这反过来限制了细菌的复制和传播。IFNg对许多其他细胞类型也具有调节作用。虽然CD 4 T细胞和IFNg在肺结核期间都很丰富，但我们目前不知道IFNg是否以及如何在这种感染期间调节CD 4 T细胞反应。使用完善的结核病小鼠模型，我们将测试IFNg直接作用于CD 4 T细胞以调节其在Mtb感染期间的分化、功能和周转的假设。我们将比较表达或不表达功能性IFNg受体的Mtb特异性CD 4 T细胞。这种方法将使我们能够解决IFNg对正常宿主环境中CD 4 T细胞的直接影响（即：所有其他细胞类型表达功能性IFNg受体）。在目的1中，我们将分析野生型和IFNg受体缺陷型Mtb特异性CD 4 T细胞在Mtb感染小鼠的肺和相关淋巴组织中的扩增和分化。目的2将解决IFNg是否在Mtb感染期间促进CD 4 T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IFNg对CD 4 T细胞的直接影响。 公共卫生相关性：结核分枝杆菌耐药性菌株的出现、有效疫苗的缺乏以及免疫抑制患者人数的不断增加（主要是由于艾滋病毒感染）促成了结核病危机。已经确定IFNg是控制Mtb感染的必需细胞因子，并且CD 4 T细胞对于分泌IFNg是关键的。然而，我们目前对IFNg如何促进CD 4 T细胞功能的了解是不够的。因此，了解IFNg在形成CD 4 T细胞分化和功能中的作用对于完整了解Mtb感染期间如何建立和维持保护性CD 4 T细胞免疫至关重要。

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.