Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
基本信息
- 批准号:10559918
- 负责人:
- 金额:$ 26.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAnimalsApoptosisCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell surfaceCellsCessation of lifeCytotoxic T-LymphocytesDataDiseaseFrequenciesFutureHIVHIV InfectionsHumanImmuneImmune System DiseasesImmune systemImmunosuppressionImmunotherapyIn VitroIncidenceInfection preventionInflammatoryInvestigationKnowledgeLigandsLigationLinkLymphocyteMediatingModelingMyeloid-derived suppressor cellsNatural Killer CellsNecrosisPathway interactionsPersonsPhysiologicalPlasmaPopulationProcessProteinsPublishingRecombinantsRecoveryRegulatory T-LymphocyteRoleSerumStimulusTNF geneTNFRSF10A geneTNFRSF10B geneTNFSF10 geneTestingTherapeuticViralWorkantiretroviral therapycancer immunotherapycell killingcell typecytotoxicgranulocyteimmune checkpointimmune checkpoint blockadeimprovedin vivoinsightmonocytemouse modelneutrophilnovelperipheral bloodpreventreceptortool
项目摘要
Elevated frequencies of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) precede and contribute to
immune dysfunction in persons living with HIV (PLHIV). The underlying mechanisms of this dysregulation are
poorly understood. Potential mechanisms under investigation include PMN-MDSCs impacting CD4+ T cell
recovery, expanding T-regulatory cells (T-reg), inducing immune checkpoints (IC), and suppressing the antiviral
functions of cytotoxic lymphocytes. While the initiation of combined antiretroviral therapy (cART) can reduce
peripheral blood PMN-MDSCs levels in PLHIV, PMN-MDSCs levels can remain elevated despite cART, and
cART does not remedy all PMN-MDSC-induced immune dysfunction. The tumor-necrosis-factor-related-
apoptosis-inducing-ligand (TRAIL) is a cell-surface and secreted apoptosis-inducing protein expressed by
activated human Natural Killer (NK) cells and cytotoxic T lymphocytes (CD8+ T cells, CTL). TRAIL ligation of its
receptors (also called death receptors (DRs)) induces apoptosis on DR-expressing cells. PMN-MDSCs express
TRAIL-R1 (DR4) and 2 (DR5). Recently published work showed a link between serum levels of agonistic soluble
TRAIL (sTRAIL) and PMN-MDSC frequency in PLHIV. Early in HIV infection, PMN-MDSC frequency inversely
correlates with plasma levels of sTRAIL, and recombinant TRAIL induces PMN-MDSC apoptosis in vitro. Thus,
DR ligation, currently being explored as an immunotherapy for cancer, may be a way to reduce PMN-MDSCs
frequencies in PLHIV. In addition to TRAIL, PMN-MDSCs also express NKG2D-ligands. NKG2D is an NK cell
activating receptor and a positive costimulatory receptor of human CTLs, and NKG2D-ligand expression renders
PMN-MDSCs highly susceptible to NK cell killing. However, despite data implicating PMN-MDSCs as essential
contributors to immune dysfunction and HIV disease, approaches targeting PMN-MDSCs in PLHIV have yet to
be explored. Using a mouse model with a competent and HIV susceptible humanized immune system, we found
that PMN-MDSCs expand rapidly upon HIV infection. Like in humans, PMN-MDSCs correlated positively with
HIV viral titers and T-reg in this model. Mechanistic studies in cytotoxic lymphocyte-depleted animals revealed
that NK cells and perhaps also CTLs controlled PMN-MDSC expansion, expressed NKG2D, and upregulated
TRAIL upon HIV infection. We propose to explore the mechanisms by which PMN-MDSC and consequent Treg
expansions are controlled. We propose to test the hypothesis that therapeutic PMN-MDSCs reduction during
HIV infection prevents PMN-MDSCs-caused immune dysfunction, improving viral control. Our studies will
leverage novel tools and therapeutic approaches to define the impact of the TRAIL and NKG2D pathways on
controlling PMN-MDSC and resultant Treg expansion upon HIV infection. We will explore therapeutic strategies
to reduce PMN-MDSC and prevent T-reg expansion upon HIV infection in vivo. The knowledge gained from our
work will facilitate new insight into the mechanisms that control or exacerbate HIV-infection-induced immune
disturbance and disease.
粒细胞髓系衍生抑制细胞(PMN-MDSCs)频率升高先于并参与了
艾滋病毒携带者免疫功能障碍(PLHIV)。这种监管失调的潜在机制是
人们对此知之甚少。正在研究的潜在机制包括PMN-MDSCs影响CD4+T细胞
恢复、扩增T调节细胞(T-reg)、诱导免疫检查点(IC)和抑制抗病毒
细胞毒性淋巴细胞的功能。而联合抗逆转录病毒疗法(CART)的启动可以减少
PLHIV中的外周血PMN-MDSCs水平、PMN-MDSCs水平在CART后仍可保持较高水平
CART不能完全纠正PMN-MDSC诱导的免疫功能障碍。肿瘤坏死因子相关的-
凋亡诱导配体(TRAIL)是一种细胞表面和分泌的凋亡诱导蛋白,表达于
激活的人自然杀伤细胞(NK)和细胞毒性T淋巴细胞(CD8+T细胞,CTL)。ITS的TRAIL结扎
受体(也称为死亡受体(DRS))诱导表达DR的细胞发生凋亡。PMN-MDSCs Express
TRAIL-R1(DR4)和2(DR5)。最近发表的研究表明,血清可溶性激动剂水平之间存在联系
PLHIV患者TRAIL(STRAIL)和PMN-MDSC频率。在HIV感染的早期,PMN-MDSC的频率相反
与血浆sTRAIL水平相关,重组TRAIL体外诱导PMN-MDSC凋亡。因此,
DR结扎术目前正在探索用于癌症的免疫疗法,可能是减少PMN-MDSCs的一种方法
PLHIV中的频率。除TRAIL外,PMN-MDSCs还表达NKG2D-配体。NKG2D是一种NK细胞
激活的人CTL受体和阳性的共刺激受体,以及NKG2D配体的表达
PMN-MDSCs对NK细胞杀伤高度敏感。然而,尽管有数据表明PMN-MDSCs是必不可少的
免疫功能障碍和HIV疾病的贡献者,针对PLHIV的PMN-MDSCs的方法尚未
被探索。使用具有能力和对艾滋病毒敏感的人源化免疫系统的小鼠模型,我们发现
PMN-MDSCs在感染艾滋病毒后迅速扩张。与人类一样,PMN-MDSCs与
这个模型中的HIV病毒滴度和T-reg。细胞毒性淋巴细胞耗竭动物的机制研究揭示
NK细胞和CTL控制PMN-MDSC的扩增,表达NKG2D,并上调
追踪艾滋病毒感染情况。我们建议探索PMN-MDSC和随后的Treg的机制
扩张得到了控制。我们建议检验这一假设,即治疗性PMN-MDSCs在
HIV感染可预防PMN-MDSCs引起的免疫功能障碍,改善病毒控制。我们的研究将
利用新的工具和治疗方法来确定TRAIL和NKG2D通路对
控制PMN-MDSC和由此产生的针对HIV感染的Treg扩张。我们将探索治疗策略
目的:减少PMN-MDSC,防止体内HIV感染时T-reg的扩张。从我们的研究中获得的知识
这项工作将有助于对控制或加剧艾滋病毒感染诱导免疫的机制有新的了解
骚乱和疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Silke Paust其他文献
Silke Paust的其他文献
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{{ truncateString('Silke Paust', 18)}}的其他基金
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10753849 - 财政年份:2023
- 资助金额:
$ 26.63万 - 项目类别:
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10931141 - 财政年份:2023
- 资助金额:
$ 26.63万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10924725 - 财政年份:2023
- 资助金额:
$ 26.63万 - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10674910 - 财政年份:2022
- 资助金额:
$ 26.63万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10561720 - 财政年份:2021
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How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10374918 - 财政年份:2021
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Mechanisms of Protection of Universal Therapeutic Antibodies to Influenza A
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10078587 - 财政年份:2019
- 资助金额:
$ 26.63万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
8996549 - 财政年份:2015
- 资助金额:
$ 26.63万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
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- 批准号:
9204387 - 财政年份:2015
- 资助金额:
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Harnessing NK Memory To Protect Against HIV Infection
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9430685 - 财政年份:2015
- 资助金额:
$ 26.63万 - 项目类别:
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