Dendritic Cell Dynamics in Peripheral and Lymphoid Tissues in SIV Infection

描述(申请人提供)：树突状细胞(DC)是专业的抗原提呈细胞，在对病原体的先天性和获得性免疫反应中起关键作用。树突状细胞在人类和非人灵长类动物中以两种主要亚群存在，即经典或髓系树突状细胞(MDC)和浆细胞样树突状细胞(PDC)。在人类免疫缺陷病毒1型(HIV)感染者的循环中，MDC和PDC会丢失，这被认为是由于循环细胞重新聚集到淋巴组织，并与疾病的进展有关。PDC向淋巴结募集的提议被用来解释HIV感染者淋巴结中干扰素-α的表达增加，这反过来又与肿瘤坏死因子相关的凋亡诱导配体(TRAIL)介导的CD4+T细胞凋亡有关。然而，感染对淋巴组织中DC亚群的影响在很大程度上仍不清楚。使用恒河猴/猴免疫缺陷病毒(SIV)模型，我们发现在病毒血症高峰期，淋巴结中的DC数量增加，这与通过炎症重新募集的情况一致。然而，在猿猴艾滋病期间，树突状细胞从血液、外周和肠系膜淋巴结和脾中耗尽，并在皮肤中密度降低。这些数据表明，在SIV感染期间，DC在淋巴组织中的募集和随后的丢失是一个高度动态的过程。我们的建议旨在这些新发现的基础上，特别关注DC损失的机制(S)。我们的初步数据表明，患有艾滋病的猴子的淋巴结树突状细胞在培养过程中被激活，并容易自发死亡。我们假设，在致病性SIV感染期间，淋巴组织中DC的丢失主要是由与慢性炎症和激活相关的因素介导的。为了验证这一假设，我们将综合分析SIVmac251经阴道接种恒河猴后血液和组织中的DC亚群。我们将在一组动物身上进行抗逆转录病毒治疗(ART)，这将有助于通过减少免疫激活来剖析细胞丢失的机制。我们将(1)确定SIV感染中DC的动力学和活化及其与组织炎症的关系；(2)确定直接感染在SIV感染中DC丢失中的作用；(3)确定细胞凋亡在SIV感染过程中DC丢失中的作用；(4)确定SIV感染过程中PDC和MDC产生干扰素-α和Th1刺激细胞因子的能力。这些研究将极大地促进我们对复杂的DC生物学在HIV感染中的理解。

DESCRIPTION (provided by applicant): Dendritic cells (DC) are professional antigen-presenting cells that are critical in the innate and acquired immune response to pathogens. DC exist as two major subsets in humans and nonhuman primates, being classical or myeloid DC (mDC) and plasmacytoid DC (pDC). mDC and pDC are lost from the circulation in human immunodeficiency virus type 1 (HIV)-infected individuals, which is thought to be due to recruitment of circulating cells to lymphoid tissues and is associated with progression to disease. The proposed recruitment of pDC to lymph nodes has been used to explain the increased expression of IFN-a in lymph nodes in HIV- infected individuals, which in turn has been linked to TNF-related apoptosis-inducing ligand (TRAIL)-mediated CD4+ T cell apoptosis. However, the effects of infection on DC subsets in lymphoid tissues remain largely unexplored. Using the rhesus macaque/simian immunodeficiency virus (SIV) model, we have shown that DC numbers are increased in lymph nodes at the peak of viremia, consistent with recruitment through inflammation. However, during simian AIDS, DC are depleted from blood, peripheral and mesenteric lymph nodes and spleen, and are reduced in density in skin. These data suggest a highly dynamic process of DC recruitment to and subsequent loss from lymphoid tissues during SIV infection. Our proposal aims to build on these novel findings, focusing in particular on the mechanism(s) of DC loss. Our preliminary data indicate that lymph node DC in monkeys with AIDS are activated and prone to spontaneous death in culture. We hypothesize that DC loss from lymphoid tissues during pathogenic SIV infection is primarily mediated by factors relating to chronic inflammation and activation. To test this hypothesis we will comprehensively analyze DC subsets in blood and tissues after intravaginal inoculation of rhesus macaques with SIVmac251. We will administer antiretroviral therapy (ART) in a subset of animals, which will aid in dissecting the mechanism of cell loss by reducing immune activation. We will (1) Determine DC kinetics and activation and the relationship to tissue inflammation in SIV infection; (2) Determine the role of direct infection in DC loss in SIV infection; (3) Determine the role of apoptosis in DC loss during SIV infection and (4) Determine the capacity for pDC and mDC to produce IFN-a and Th1-stimulating cytokines during SIV infection. These studies will greatly advance our understanding of complex DC biology in HIV infection.