Immunopathogenesis of Histoplasmosis and TNF

项目描述 致病真菌，组织胞浆菌，是美国中西部和东南部的地方病， 呼吸道真菌感染的最常见原因。T细胞介导的免疫的激活被认为是 是宿主控制感染的主要机制。虽然大多数感染是温和的，在免疫抑制 个人可能会危及生命。肿瘤坏死因子（TNF）-α拮抗剂是目前应用较多的肿瘤坏死因子受体拮抗剂之一。 常见的免疫抑制药物，破坏免疫力，易患组织胞浆菌病。 这些药物改善了许多炎症性疾病患者的生活，但却使他们面临传播的风险。 艾德组织胞浆菌病和人类一样，小鼠中TNF-α的中和作用使其对真菌的免疫力丧失。在受感染 在给予抗-TNF-α的小鼠中，我们发现常规的肺Foxp 3-CD 4 + T细胞抑制IFN-γ的能力。 刺激M细胞杀死酵母细胞。在这个群体中，我们鉴定了Foxp 3-CD 4 + CD 25- T细胞的存在。 在一些实施方案中，抑制性受体是携带多种抑制性受体的亚组，包括但不限于PD-1、Tim-3和TIGIT。我们推测 这种T细胞亚群解除了活化的巨噬细胞和树突细胞的生长抑制特性。 在第一个目标中，我们将1）确定该亚群是否直接损害用IFN-γ或GM刺激的M β的能力， CSF或树突状细胞以消除真菌; 2）确定通过TNF受体1或2的信号传导是否是 该群体的出现，以及3）确定这些细胞是否在体内负调节免疫。在 第二个目标，我们将检查这些细胞的转录组，以确定促进细胞增殖的调控元件。 抑制性受体表达增加。同时，我们将研究这些细胞的代谢特性， 以确定代谢的变化是否可以解释抑制性受体的上调。我们将团结 代谢与RNA-seq，以确定代谢和转录组学之间的互连网络 这些研究将为TNF-α拮抗作用背景下的T细胞生物学提供新的见解。

Project Description The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and is the most frequent cause of respiratory fungal infection. Activation of T cell-mediated immunity is considered to be a major mechanism for host control of infection. Although most infections are mild, in immunosuppressed individuals it may become life-threatening. The tumor necrosis factor (TNF)- antagonists are one of the more common immunosuppressive drugs that undermine immunity and predispose to progressive histoplasmosis. These agents have improved the lives of many with inflammatory diseases yet put them at risk for disseminat- ed histoplasmosis. As in humans, neutralization of TNF- in mice disables immunity to the fungus. In infected mice given anti-TNF-we discovered that conventional lung Foxp3-CD4+ T cells inhibited the ability of IFN-- stimulated M to kill yeast cells. Within this population, we identified the presence of a Foxp3-CD4+CD25- T cell subset that bears multiple inhibitory receptors including but not limited to PD-1, Tim-3, and TIGIT. We postulate this T cell subpopulation disarms the growth inhibitory properties of activated macrophages and dendritic cells. In the first aim we will 1) determine if this subset directly impairs the ability of M stimulated with IFN- or GM- CSF or dendritic cells to eliminate the fungus; 2) determine if signaling through TNF receptor 1 or 2 is key for the emergence of this population, and 3) ascertain if these cells negatively regulate immunity in vivo. In the second aim, we will examine the transcriptome of these cells to identify regulatory elements that prompt the increased expression of inhibitory receptors. In parallel, we will examine the metabolic properties of these cells to determine if changes in metabolism may account for the upregulation in inhibitory receptors. We will unite metabolism with RNA-seq to identify interconnecting networks between metabolism and transcriptomics These studies will provide new insights into the biology of T cells in the context of TNF- antagonism.