HIV-induced immune activation impairs immune reconstitution through S1P
HIV 诱导的免疫激活通过 S1P 损害免疫重建
基本信息
- 批准号:8502423
- 负责人:
- 金额:$ 16.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-02 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAgonistCCL25 geneCD34 geneCD34+ precursorCXCR4 geneCell surfaceCellsDataDevelopmentDown-RegulationEmigrantEpithelial CellsExposure toHIVHIV InfectionsHIV-1Hematopoietic stem cellsHumanImmuneImpairmentIn VitroIndividualInfectionInflammatoryInterferonsInterleukin-6Interleukin-7LiteratureLymphoid TissueMethodsMigration AssayMolecularMusNatural regenerationPeripheralPlayProcessReagentReceptor SignalingRoleSELL geneSphingosine-1-Phosphate ReceptorStem cellsStromal Cell-Derived Factor 1T memory cellT-Cell DevelopmentT-LymphocyteT-Lymphocyte SubsetsTNF geneTestingTherapeutic InterventionThymus GlandUp-Regulationantiretroviral therapybasechemokinecytokinehuman migrationimmune activationinsightmouse modelnovelnovel strategiesperipheral bloodreceptorreceptor expressionreconstitutionresearch studyresponsesphingosine 1-phosphatethymocyte
项目摘要
DESCRIPTION (provided by applicant): Persistent immune activation in HIV-1 infected individuals, characterized by increased levels of pro- inflammatory cytokines, such as IL-7, IL-6, IFN-?, TNF-??, and expression of activation markers, including CD69, is associated with a lack of T cell regeneration despite successful antiretroviral therapy. Lack of T cell regeneration is likely due in part to a decrease in entry of hematopoietic stem cells into the thymus and egress of naive T cells from the thymus to the periphery. However, there are no data available elucidating these processes in humans. From studies in the mouse it has become apparent that Sphingosine-1-phosphate (S1P) and one of its receptors, S1P receptor-1 (S1P-R1) play essential roles in egress of naive T cells from the thymus to the periphery as well as egress of memory T cells from the secondary lymphoid tissues. There is also evidence that S1P controls expression of chemokines like CCL25 by thymic endothelial and cortical epithelial cells and thereby entry of precursors into the murine thymus. In addition, S1P enhances SDF-1??/CXCR4 migration of human CD34+ cells. Together these data suggest that S1P plays an important role in entry of CD34+ precursors into the thymus as well as egress of naive T cells from the thymus to the periphery. In addition to S1P receptor expression, the CD69 molecule has been found to play a role in regulating thymocyte egress. CD69 is known as an early activation molecule in the periphery. In the thymus CD69 is expressed during positive and negative selection, but is not present on recent thymic emigrants. Our novel preliminary data in the human thymus show that only mature CD69- thymocytes (CD3hiCD27+CD45RA+ CD62L+CD69-), which are phenotypically identical to naive peripheral blood T cells, can respond to S1P and emigrate out of the thymus in response to S1P. This effect is inhibited by FTY720, an S1P-R agonist. Interestingly, our preliminary data also shows that CD69 is upregulated on CD34+ progenitor cells after exposure to IL-7 and IFN-??. Thus, based on murine data in the literature and our preliminary data with human CD34+ cells and thymocytes we hypothesize that HIV-1 induced immune activation increases expression of CD69 leading to downregulation of S1P-R1, thereby interfering with entry of CD34+ cells into and egress of mature CD69- thymocytes out of the thymus to the periphery. We will use our established methods as well as novel approaches and unique reagents to test our hypothesis. Experiments will be performed with HIV-infected humanized mouse models and in vitro T cell development and migration assays as proposed in the following specific aims: 1. To investigate the effect of HIV-induced immune activation on S1P and its receptors on entry of CD34+ hematopoietic stem cells into the thymus. 2. To determine whether HIV infection affects egress of nave T lymphocyte subsets from the thymus to the periphery through changes in S1P receptor expression. The present proposal represents a unique collaborative approach to elucidate the role of HIV induced immune activation on T cell development and reconstitution of peripheral naive T cells in HIV-1 infection. Insights into the mechanisms underlying the impairment of precursor entry into and exit of naive T cells out of the thymus will enable the development of immunomodulatory therapeutic interventions to counteract impaired T cell development and regeneration.
描述(由申请方提供):HIV-1感染个体的持续免疫激活,特征为促炎细胞因子水平升高,如IL-7、IL-6、IFN-?、TNF-α,活化标志物,包括CD 69的表达,与尽管成功的抗逆转录病毒治疗但缺乏T细胞再生有关。缺乏T细胞再生可能部分是由于造血干细胞进入胸腺和幼稚T细胞从胸腺到外周的排出减少。然而,没有可用的数据阐明人类的这些过程。从小鼠的研究中,很明显,鞘氨醇-1-磷酸(S1 P)及其受体之一,S1 P受体-1(S1 P-R1)在幼稚T细胞从胸腺到外周的流出以及记忆T细胞从次级淋巴组织的流出中发挥重要作用。也有证据表明,S1 P控制胸腺内皮和皮质上皮细胞的趋化因子如CCL 25的表达,从而使前体进入小鼠胸腺。此外,S1 P增强了SDF-1??/人CD 34+细胞的CXCR 4迁移。总之,这些数据表明,S1 P在CD 34+前体进入胸腺以及幼稚T细胞从胸腺到外周的排出中起重要作用。除了S1 P受体的表达外,已经发现CD 69分子在调节胸腺细胞排出中起作用。CD 69被认为是外周中的早期活化分子。在胸腺中,CD 69在阳性和阴性选择过程中表达,但在最近的胸腺移民中不存在。我们在人胸腺中的新的初步数据表明,只有成熟的CD 69-胸腺细胞(CD 3 hiCD 27 + CD 45 RA + CD 62 L + CD 69-),这是表型相同的幼稚外周血T细胞,可以响应S1 P和移民的胸腺响应S1 P。这种作用被S1 P-R激动剂FTY 720抑制。有趣的是,我们的初步数据还显示,暴露于IL-7和IFN-γ后,CD 34+祖细胞上的CD 69上调。因此,根据文献中的小鼠数据和我们对人CD 34+细胞和胸腺细胞的初步数据,我们假设HIV-1诱导的免疫活化增加了CD 69的表达,导致S1 P-R1的下调,从而干扰了CD 34+细胞进入和成熟CD 69-胸腺细胞从胸腺到外周的流出。我们将使用我们建立的方法以及新的方法和独特的试剂来测试我们的假设。实验将使用HIV感染的人源化小鼠模型和体外T细胞发育和迁移测定进行,如以下具体目的所提出的:1.探讨HIV免疫激活对S1 P及其受体在CD 34+造血干细胞进入胸腺中的作用。 2.确定HIV感染是否通过S1 P受体表达的变化影响幼稚T淋巴细胞亚群从胸腺到外周的流出。本提案代表了一种独特的合作方法,以阐明HIV诱导的免疫激活对HIV-1感染中T细胞发育和外周幼稚T细胞重建的作用。对幼稚T细胞进入和离开胸腺的前体损伤的潜在机制的了解将使免疫调节治疗干预的发展能够抵消受损的T细胞发育和再生。
项目成果
期刊论文数量(0)
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Christel H. Uittenbogaart其他文献
Focal glomerulosclerosis and renal transplantation
- DOI:
10.1016/s0022-3476(79)80660-5 - 发表时间:
1979-08-01 - 期刊:
- 影响因子:
- 作者:
Mohammad H. Malekzadeh;Eva T. Heuser;Robert B. Ettenger;Alfred J. Pennisi;Christel H. Uittenbogaart;Barry L. Warshaw;Richard N. Fine - 通讯作者:
Richard N. Fine
Christel H. Uittenbogaart的其他文献
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{{ truncateString('Christel H. Uittenbogaart', 18)}}的其他基金
T follicular regulatory cells, a potential HIV reservoir.
滤泡调节 T 细胞,一个潜在的 HIV 储存库。
- 批准号:
8927527 - 财政年份:2014
- 资助金额:
$ 16.07万 - 项目类别:
T follicular regulatory cells, a potential HIV reservoir.
滤泡调节 T 细胞,一个潜在的 HIV 储存库。
- 批准号:
8730975 - 财政年份:2014
- 资助金额:
$ 16.07万 - 项目类别:
2014 Midwinter Conference of Immunologists at Asilomar
2014 年阿西洛玛仲冬免疫学家会议
- 批准号:
8651771 - 财政年份:2013
- 资助金额:
$ 16.07万 - 项目类别:
2014 Midwinter Conference of Immunologists at Asilomar
2014 年阿西洛玛仲冬免疫学家会议
- 批准号:
8975097 - 财政年份:2013
- 资助金额:
$ 16.07万 - 项目类别:
HIV-induced immune activation impairs immune reconstitution through S1P
HIV 诱导的免疫激活通过 S1P 损害免疫重建
- 批准号:
8411112 - 财政年份:2012
- 资助金额:
$ 16.07万 - 项目类别:
2010 Midwinter Conference of Immunologists at Asilomar
2010 年阿西洛玛仲冬免疫学家会议
- 批准号:
8011995 - 财政年份:2010
- 资助金额:
$ 16.07万 - 项目类别:
2010 Midwinter Conference of Immunologists at Asilomar
2010 年阿西洛玛仲冬免疫学家会议
- 批准号:
7916313 - 财政年份:2010
- 资助金额:
$ 16.07万 - 项目类别:
IFN-a and pDC in HIV infection: impact on T cell development and reconstitution
HIV 感染中的 IFN-a 和 pDC:对 T 细胞发育和重建的影响
- 批准号:
8138256 - 财政年份:2010
- 资助金额:
$ 16.07万 - 项目类别:
2010 Midwinter Conference of Immunologists at Asilomar
2010 年阿西洛玛仲冬免疫学家会议
- 批准号:
8230615 - 财政年份:2010
- 资助金额:
$ 16.07万 - 项目类别:
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