Dendritic Cell Dynamics in Peripheral and Lymphoid Tissues in SIV Infection

描述（由申请人提供）：树突状细胞（DC）是专业的抗原呈递细胞，在对病原体的先天和获得性免疫反应中起关键作用。在人类和非人灵长类动物中，DC主要分为两大亚型，即经典或髓样DC （mDC）和浆细胞样DC （pDC）。在人类免疫缺陷病毒1型（HIV）感染者中，mDC和pDC从循环中丢失，这被认为是由于循环细胞向淋巴组织募集，并与疾病进展有关。pDC向淋巴结的募集已被用来解释HIV感染个体淋巴结中IFN-a表达的增加，这反过来又与tnf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未被探索。利用恒河猴/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DC数量增加，与炎症募集一致。然而，在猿类艾滋病期间，DC从血液、外周和肠系膜淋巴结和脾脏中消失，并且在皮肤中的密度降低。这些数据表明，在SIV感染期间，DC向淋巴组织募集和随后从淋巴组织丢失是一个高度动态的过程。我们的建议旨在建立在这些新发现的基础上，特别关注直流损耗的机制。我们的初步数据表明，艾滋病猴的淋巴结DC在培养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DC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，我们将全面分析恒河猴阴道内接种SIVmac251后血液和组织中的DC亚群。我们将对一部分动物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解剖细胞损失的机制。我们将(1)确定SIV感染中DC的动力学和激活及其与组织炎症的关系；(2)确定直接感染DC丢失在SIV感染中的作用；(3)确定SIV感染时细胞凋亡在DC丢失中的作用；(4)确定pDC和mDC在SIV感染时产生IFN-a和th1刺激细胞因子的能力。这些研究将极大地促进我们对HIV感染中复杂DC生物学的理解。

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.