AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
基本信息
- 批准号:7994838
- 负责人:
- 金额:$ 36.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-01 至 2012-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAcuteAddressAntibodiesAntigensApoptosisAutologousBindingBiological AssayCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCellsChronicClonal AnergyCoculture TechniquesCultured CellsDataDevelopmentDiseaseDisease ProgressionEnzyme-Linked Immunosorbent AssayEquilibriumFailureFeline Immunodeficiency VirusFelis catusFlow CytometryGaggingHIVHIV AntigensHIV InfectionsHealthHomeostasisHumanIL2 geneIL2RA geneImmuneImmune System DiseasesImmune responseImmunosuppressionImmunosuppressive AgentsIncubatedInfectionInfectious AgentInflammatory ResponseInterferonsLabelLaboratoriesLentivirus InfectionsLymphoid TissueMaintenanceMeasurableMediatingMembraneMessenger RNAMitogensModalityMolecular ProbesNaturePatientsPeptidesPeripheralPeripheral Blood Mononuclear CellPhenotypePlasmaPlayPopulationProcessProliferatingProteinsRegulatory T-LymphocyteReverse Transcriptase Polymerase Chain ReactionRoleSamplingSelf ToleranceSerumSignal PathwaySignal TransductionSmad ProteinsSmad proteinStagingSubfamily lentivirinaeSuppressor-Effector T-LymphocytesSurfaceT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTimeTissuesTranscription Regulatory ProteinTransforming Growth Factor betaViralViral load measurementVirusVirus DiseasesWestern Blottinganergyarmimmunopathologyin vivoinhibiting antibodyneutralizing antibodypathogenpreventreceptorresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Immune suppression of self-reactive CD4+ and CD8+ T cells by natural, thymic-derived CD4+CD25+ T regulatory cells is crucial for the maintenance of peripheral self-tolerance. Recent data suggest that in addition to anti-self natural Treg cells, a population of Treg cells, activated in the peripheral lymphoid tissues by pathogens may play a major role in controlling excessive "inflammatory" responses to infection. Natural and pathogen-induced Treg cells are phenotypically and functionally similar in that they express CD25, GITR, and the transcriptional regulatory protein Foxp3, and are immunosuppressive for antigen-activated T cells, suggesting that natural and peripheral activated Treg cells may be of the same lineage. However, we have recently demonstrated in the FIV AIDS lentiviruses infection that pathogen-induced Treg cells differ from natural Treg cells in that they express TGF-2 on their surface (mTGF-2+) and that mTGF-2 mediates Treg suppressor function and may also control peripheral Treg homeostasis. The experiments proposed herein will further explore these observations to test the hypothesis that Treg cells in the peripheral immune tissues are a normal component of the immune regulatory process to infectious agents and that AIDS lentiviruses over-ride the normal controls on Treg activation and function, resulting in chronic immunosuppressive activity and abnormal Treg homeostasis. CD4+CD25+ Treg cells will be assessed phenotypically (mTGF-2+, Foxp3+) and functionally (inhibition of ConA-induced proliferation and IL2 by CD4+ Th cells and IFN-3 by CD8+ T cells) in cats acutely infected with the NCSU1 isolate of FIV. FIV gag ELISA and RT-PCR assays will be performed to determine if Treg activation is associated with virus infection. The role of mTGF-2 in Treg suppressor function will be determined by the use of TGF-2 and TGF-2RII neutralizing antibodies. To investigate the role of mTGF-2 in maintaining peripheral Treg homeostasis in FIV+ cats by recruitment from the CD4+ Th pool, we will incubate mTGF-2+ Treg cells with CD4+ Th cells and analyze the target cells for expression of CD25, Foxp3, mTGF-2 and for suppressor function. To confirm the mTGF-2+ Treg cells induced conversion of Th cells to Treg cells, we will utilize TGF-2 and TGF-2RII neutralizing antibodies to block the conversion process. These studies will address two important immunological issues: 1) how do CD4+CD25+ Treg cells mediate suppression and phenotypic conversion of CD4+ and/or CD8+ Th populations to maintain their homeostasis; and 2) how do AIDS lentivirus infections over-ride the normal controls over Treg cell activation and function, resulting in chronic Treg-induced immunosuppression, as well as abnormal Treg homeostasis. PUBLIC HEALTH RELEVANCE: T regulatory (Treg) cells play a pivotal role in maintaining the balance between protective immune responses and immunopathology associated with primary infections. We believe that AIDS lentivirus infections such as HIV over-ride the normal controls over Treg cell activation and function, resulting in chronic Treg cell activation and global immunosuppression and AIDS. Understanding how HIV co-opts this normal immune regulatory mechanism, which will be addressed in this proposal, will aid in the development of better therapeutic modalities.
描述(由申请人提供):天然胸腺来源的 CD4+CD25+ T 调节细胞对自身反应性 CD4+ 和 CD8+ T 细胞的免疫抑制对于维持外周自身耐受性至关重要。最近的数据表明,除了抗自身的天然 Treg 细胞外,外周淋巴组织中被病原体激活的 Treg 细胞群可能在控制对感染的过度“炎症”反应中发挥重要作用。天然和病原体诱导的 Treg 细胞在表型和功能上相似,因为它们表达 CD25、GITR 和转录调节蛋白 Foxp3,并且对抗原激活的 T 细胞具有免疫抑制作用,这表明天然和外周激活的 Treg 细胞可能属于同一谱系。然而,我们最近在FIV AIDS慢病毒感染中证明,病原体诱导的Treg细胞与天然Treg细胞不同,它们在表面表达TGF-2(mTGF-2+),并且mTGF-2介导Treg抑制功能,还可能控制外周Treg稳态。本文提出的实验将进一步探索这些观察结果,以检验以下假设:外周免疫组织中的 Treg 细胞是针对感染因子的免疫调节过程的正常组成部分,并且艾滋病慢病毒超越对 Treg 激活和功能的正常控制,导致慢性免疫抑制活性和异常的 Treg 稳态。对急性感染 FIV NCSU1 分离株的猫的 CD4+CD25+ Treg 细胞进行表型(mTGF-2+、Foxp3+)和功能评估(CD4+ Th 细胞抑制 ConA 诱导的增殖和 IL2,CD8+ T 细胞抑制 IFN-3)。将进行 FIV gag ELISA 和 RT-PCR 检测以确定 Treg 激活是否与病毒感染相关。 mTGF-2 在 Treg 抑制功能中的作用将通过使用 TGF-2 和 TGF-2RII 中和抗体来确定。为了研究 mTGF-2 通过从 CD4+ Th 池招募来维持 FIV+ 猫外周 Treg 稳态的作用,我们将 mTGF-2+ Treg 细胞与 CD4+ Th 细胞一起孵育,并分析靶细胞的 CD25、Foxp3、mTGF-2 表达和抑制功能。为了确认 mTGF-2+ Treg 细胞诱导 Th 细胞向 Treg 细胞的转化,我们将利用 TGF-2 和 TGF-2RII 中和抗体来阻断转化过程。这些研究将解决两个重要的免疫学问题:1)CD4+CD25+Treg细胞如何介导CD4+和/或CD8+Th群体的抑制和表型转化以维持其稳态; 2) 艾滋病慢病毒感染如何超越对 Treg 细胞激活和功能的正常控制,导致慢性 Treg 诱导的免疫抑制以及异常的 Treg 稳态。公共卫生相关性:调节性 T (Treg) 细胞在维持保护性免疫反应和与原发感染相关的免疫病理学之间的平衡方面发挥着关键作用。我们认为,HIV 等艾滋病慢病毒感染超越了对 Treg 细胞激活和功能的正常控制,导致慢性 Treg 细胞激活和整体免疫抑制和艾滋病。了解艾滋病毒如何利用这种正常的免疫调节机制(本提案将讨论这一点)将有助于开发更好的治疗方式。
项目成果
期刊论文数量(0)
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Mary B Tompkins其他文献
Mary B Tompkins的其他文献
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{{ truncateString('Mary B Tompkins', 18)}}的其他基金
AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
- 批准号:
8197195 - 财政年份:2008
- 资助金额:
$ 36.51万 - 项目类别:
AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
- 批准号:
7619371 - 财政年份:2008
- 资助金额:
$ 36.51万 - 项目类别:
AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
- 批准号:
7739491 - 财政年份:2008
- 资助金额:
$ 36.51万 - 项目类别:
Cytomation MoFlo cytometer and high-speed cell sorter
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- 批准号:
6581548 - 财政年份:2003
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$ 36.51万 - 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
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6646453 - 财政年份:1995
- 资助金额:
$ 36.51万 - 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV INFECTED CATS
五只受感染的猫失去 TH1 免疫功能
- 批准号:
2075116 - 财政年份:1995
- 资助金额:
$ 36.51万 - 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
- 批准号:
6213558 - 财政年份:1995
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$ 36.51万 - 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
- 批准号:
6747354 - 财政年份:1995
- 资助金额:
$ 36.51万 - 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV INFECTED CATS
五只受感染的猫失去 TH1 免疫功能
- 批准号:
2672521 - 财政年份:1995
- 资助金额:
$ 36.51万 - 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
- 批准号:
6373478 - 财政年份:1995
- 资助金额:
$ 36.51万 - 项目类别:
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