Immunopathogenesis of Histoplasmosis and TNF

项目说明 致病真菌，组织胞浆菌，是美国中西部和东南部特有的， 呼吸道真菌感染最常见的原因。激活T细胞介导的免疫被认为是 是宿主控制感染的主要机制。尽管大多数感染都是轻微的，但在免疫抑制的情况下 对个人来说，它可能会危及生命。肿瘤坏死因子-拮抗剂是 破坏免疫力并易患进行性组织胞浆菌病的常见免疫抑制药。 这些药物改善了许多炎症性疾病患者的生活，但也使他们面临传播的风险- ED组织胞浆菌病。与人类一样，中和小鼠体内的肿瘤坏死因子-会使人对这种真菌失去免疫力。在受感染的地方 小鼠给予抗肿瘤坏死因子-后发现，常规肺Foxp3-+T细胞抑制干扰素-CD8- 刺激M-杀死酵母细胞。在这个人群中，我们确定了Foxp3-CD4+CD25-T细胞的存在 携带多种抑制受体的亚群，包括但不限于PD-1、TIM-3和TIGIT。我们假设 这个T细胞亚群解除了激活的巨噬细胞和树突状细胞的生长抑制特性。 在第一个目标中，我们将1)确定这一亚群是否直接损害由干扰素-或GM-刺激的M-CFU的能力。 通过脑脊液或树突状细胞清除真菌；2)确定通过肿瘤坏死因子受体1或2的信号是关键 这一群体的出现，以及3)确定这些细胞是否在体内负向调节免疫。在 第二个目标，我们将检查这些细胞的转录组，以确定促使 抑制受体表达增加。同时，我们将检查这些细胞的代谢特性 以确定新陈代谢的变化是否可以解释抑制性受体的上调。我们将团结一致 用rna-seq鉴定新陈代谢和转录组学之间的相互连接网络 研究将在肿瘤坏死因子-拮抗的背景下为T细胞的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.