Interferon gamma Regulation of CD4 T Cell Responses in Tuberculosis

描述（由申请人提供）：结核病是一个重大的公共卫生问题。结核病的病原体结核分枝杆菌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，免疫系统无法完全清除感染，这种感染持续存在于巨噬细胞中。本提案的主要目的是阐明结核病期间调节免疫的机制。结核分枝杆菌感染的控制归因于分泌干扰素γ (IFNg)的T辅助型1 CD4 T细胞。IFNg激活巨噬细胞，诱导活性氮和氧中间体的产生，从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。虽然在结核病期间，CD4 T细胞和IFNg在肺部都很丰富，但我们目前尚不清楚IFNg是否以及如何调节这种感染期间的CD4 T细胞反应。利用一种成熟的小鼠结核病模型，我们将验证IFNg直接作用于CD4 T细胞以调节其在结核分枝杆菌感染期间的分化、功能和转换的假设。我们将比较mtb特异性CD4 T细胞是否表达功能性IFNg受体。这种方法将使我们能够在正常宿主环境（即所有其他细胞类型表达功能性IFNg受体）中解决IFNg对CD4 T细胞的直接影响。在Aim 1中，我们将分析野生型和IFNg受体缺陷型Mtb特异性CD4 T细胞在Mtb感染小鼠肺部和相关淋巴组织中的扩增和分化。目的2将探讨IFNg是否促进Mtb感染期间CD4 T细胞的收缩和/或周转。在目标3中，我们将在分子水平上讨论IFNg对CD4 T细胞的直接影响。

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.