Homeostasis of T cells in primates

描述(申请人提供)：对灵长类T细胞稳态调节机制知之甚少。该项目的总体目标是研究通过抗体诱导的特定T细胞亚群的耗尽来调节健康恒河猴(RM)和黑尾猴(SM)的T细胞的动态平衡。我们相信这项建议与爱滋病研究有关，因为这两个物种的SIV感染有其独特的特点，即在红斑狼疮中致病，而在红斑狼疮中不具致病性。如果我们的研究确定了RM和SM在T细胞稳态方面的差异，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发现，尽管在致病性和非致病性感染期间，由于病毒的细胞病变作用，CD4T细胞都会丢失，但只有在病原性感染中，T细胞的动态平衡才会丢失。这一观察结果表明，T细胞稳态的失稳可能在艾滋病的发病机制中起作用，旨在重建这种稳态的治疗方法可能被用于HIV感染患者的临床治疗。在这里，我们建议通过对骨髓(BM)、外周血(PB)和淋巴结(LN)进行顺序采样来研究CD4和CD8T细胞耗尽后淋巴细胞的再繁殖。进行的分析将包括：(1)免疫表型研究，(2)最近胸腺移民水平的测定，以及(3)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水平的检测。在这项应用中，我们还建议通过在正常动物和胸腺切除动物中进行CD4和CD8T细胞去除来评估胸腺在T细胞动态平衡中的作用。我们认为，这项比较研究可能提供以下信息：(1)骨髓、层粘连蛋白和胸腺在T细胞稳态中的不同作用；(2)CD4和CD8T细胞稳态的特殊特征；(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尽的T细胞群中的作用。重要的是，这种方法可能允许我们定义在RM和SM中维持T细胞稳态的方式的差异，这可能为SIV感染在这两个物种中的显著不同影响提供线索。总之，我们相信这个项目可能会为灵长类T细胞的动态平衡以及这种动态平衡的失稳如何在艾滋病的发病机制中发挥作用提供有用的信息。

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.