T REGULATORY CELLS IN AFRICAN GREEN MONKEYS AND RHESUS MACAQUES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Tregs最初被定义为CD4+CD25+，在小鼠和人类中抑制T细胞的激活和增殖。由于慢性免疫激活和T细胞的快速更新是人类和Rh病理性HIV/SIVmac感染的特征，这些细胞可能在HIV/SIV的发病机制中发挥重要作用。RH和AGMS是研究SIV发病机制的最佳模型。它们在一个基本方面不同：感染SIVmac的Rh会发展成艾滋病，而感染其特定物种的SIVagm的AGM在很长一段时间内都保持健康。我们的初步研究表明，在SIVmac感染的Rh中，CD4+CD25+T细胞丢失，这可能解释了在这种病原性感染中描述的异常的慢性T细胞过度激活。相反，我们发现在SIVagm感染的非常早期阶段，Tregs的数量增加了。为了明确Tregs在致病性和非致病性SIV感染中的作用，我们在这个项目中设计了针对正常、未感染的Rh和AGM的实验，以证实功能Tregs的存在，并验证我们操纵这一T细胞亚群的能力。 我们首先刻画了Rh和AGM中的Tregs。由于CD25不是Tregs的特异性标记物，我们将重点放在鉴定Tregs的特异性标记物，如FOXP3、GITR、CD127和NeuroPilin-1，以及以前研究的CD4+CD25+T细胞。我们还通过测定CD4+CD25+T细胞的体外抑制功能，证实了在非人类灵长类动物中存在功能齐全的Tregs。我们测定了Tregs在Rh和AGM组织中的分布。我们发现，大多数Treg细胞存在于血液和LNS中，只有少数FOXP3阳性细胞位于肠道中。我们还验证了现有的抗CD25阻断/耗竭药物在体外和体内消除Rh和AGM中Tregs的能力。结合起来，这些实验旨在描述和操纵猿猴树细胞，以检验这些细胞在艾滋病发病机制中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tregs were initially defined as CD4+CD25+, suppress T-cell activation and proliferation in mice and humans. As chronic immune activation and rapid turnover of T cells are hallmarks of pathogenic HIV/SIVmac infections in humans and Rh, these cells may play an important role in HIV/SIV pathogenesis. Rh and AGMs are the best models for the study of SIV pathogenesis. They differ in one fundamental aspect: while Rh infected with SIVmac develop AIDS, AGMs infected with their species-specific SIVagm remain healthy for long periods of time. Our preliminary studies showed a loss of CD4+CD25+ T cells in SIVmac-infected Rh that may explain the aberrant chronic T cell hyperactivation described in this pathogenic infection. In contrast, we have found an increase in the number of Tregs during very early stages of SIVagm infection. To clearly define the role of Tregs in pathogenic and non-pathogenic SIV infections, we designed experiments in this project for normal, uninfected Rh and AGMs, to confirm the existence of functional Tregs and to verify our ability to manipulate this T cell subset. We first characterized Tregs in Rh and AGMs. As CD25 is not a specific marker for Tregs; we focused on identification of specific markers for Tregs such as FOXP3, GITR, CD127 and neuropilin-1 in association with previously studied CD4+CD25+ T cells. We also confirmed the existence of fully functional Tregs in non-human primates by determining the in vitro suppressive functions of CD4+CD25+ T cells. We determined the distribution of Tregs in tissues in Rh and AGMs. We showed that the majority of Tregs are present in blood and LNs and only few FOXP3 positive cells are located in the intestine. We also verified the capacity of available anti-CD25 blocking/depleting drugs to eliminate Tregs in Rh and AGMs in vitro and in vivo. Combined, these experiments were designed to characterize and manipulate simian Tregs in order to examine the role of these cells in AIDS pathogenesis.