Homeostasis of T cells in primates

描述（由申请人提供）：对灵长类动物中调节T细胞稳态的机制知之甚少。本课题的总体目标是通过抗体诱导的特异性T细胞亚群的耗竭来研究健康恒河猴（RM）和白眉猴（SM）T细胞的稳态调节。我们认为，这一建议是有关艾滋病的研究，由于SIV感染的具体特点，在这两个物种，即致病性RM和非致病性SM。如果我们的研究确定RM和SM之间T细胞稳态的差异，那么我们可以假设这些差异在决定SIV感染后的临床结果中发挥作用。在早期的研究中，我们表明，虽然CD 4 + T细胞在致病性和非致病性感染期间由于病毒的细胞病变效应而丢失，但只有在致病性感染中T细胞的稳态丢失。这一观察结果表明，T细胞稳态的失败可能在艾滋病的发病机制中发挥作用，旨在重建这种稳态的治疗方法可用于HIV感染患者的临床管理。在这里，我们建议研究淋巴细胞再生后，CD 4+和CD 8 + T细胞耗竭，依次采样骨髓（BM），外周血（PB）和淋巴结（LN）。所进行的分析将包括：（1）免疫表型研究，（2）测定近期胸腺移出的水平，和（3）检查可能在T细胞稳态中起作用的细胞因子（即IL-7、IL-15和IL-2）的水平。在本申请中，我们还建议通过在正常和胸腺切除动物中进行CD 4+和CD 8 + T细胞耗竭来评估胸腺在T细胞稳态中的作用。我们认为，这项比较研究可能提供以下信息：（1）BM、LN和胸腺在T细胞稳态中的不同作用;（2）CD 4+和CD 8 + T细胞稳态的具体特征;（3）通过稳态机制增殖的T细胞的免疫表型;（4）细胞因子在重建急性耗竭的T细胞群中的作用。重要的是，这种方法可以让我们定义T细胞稳态的方式在RM与SM，这可以提供线索，在两个物种的SIV感染的显着不同的影响保持的差异。总之，我们相信，这个项目可能提供有用的信息，在灵长类动物的T细胞的稳态，以及如何失败的这种稳态可能在艾滋病的发病机制中发挥作用。

DESCRIPTION (provided by applicant): Little is known about the mechanisms regulating T cell homeostasis in primates. The overall aim of this project is to study the homeostatic regulation of T cells in healthy rhesus macaques (RM) and sooty mangabeys (SM) via antibody-induced depletion of specific T cell subsets. We believe that this proposal is relevant to AIDS research due to the specific features of SIV-infection in the two species, i.e. pathogenic in RM and non-pathogenic in SM. If our study identifies differences in T cell homeostasis between RM and SM, we may then hypothesize that these differences play a role in determining the clinical outcome after SIV-infection. In earlier studies we showed that although CD4+ T cells are lost due to the cytopathic effect of the virus during both pathogenic and non-pathogenic infections, only in pathogenic infections is the homeostasis of T cells lost. This observation suggests that the failure of T cell homeostasis may play a role in the pathogenesis of AIDS, and that treatments aimed at reconstituting this homeostasis may be used in the clinical management of HIV-infected patients. Here we propose to study the lymphocyte repopulation that follows CD4+ and CD8+ T cell depletion by sequentially sampling bone marrow (BM), peripheral blood (PB) and lymph nodes (LN). The performed analyses will include: (1) immunophenotypic studies, (2) determination of levels of recent thymic emigrants, and (3) examination of levels of cytokines, i.e. IL-7, IL-15and IL-2, that may play a role in T cell homeostasis. In this application we also propose to evaluate the role of the thymus in T cell homeostasis by performing CD4+ and CD8+ T cell depletions in both normal and thymectomized animals. We believe that this comparative study may provide information on (1) the differential role of BM, LN and thymus in T cell homeostasis; (2) the specific features of the homeostasis ofCD4+ and CD8+ T cells; (3) the immunophenotype of T cells that are proliferating via homeostatic mechanisms; and (4) the role of cytokines in reconstituting acutely depleted T cell populations. Importantly, this approach may allow us to define differences in the way T cell homeostasis is maintained in RM vs SM, which could provide clue regarding the markedly different impact of SIV-infection in the two species. In all, we believe that this project may provide useful information on the homeostasis of T cells in primates, and how the failure of this homeostasis may play a role in the pathogenesis of AIDS.