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:10674910
- 负责人:
- 金额:$ 3.54万
- 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 2023-08-25
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeActivated Natural Killer CellAnimalsApoptosisCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell surfaceCellsCessation of lifeCytotoxic T-LymphocytesDataDiseaseFrequenciesFutureHIVHIV InfectionsHumanImmuneImmune System DiseasesImmune systemImmunosuppressionImmunotherapyIn VitroIncidenceInduction of ApoptosisInfection preventionInflammatoryInvestigationKnowledgeLigandsLigationLinkLymphocyteLymphocyte DepletionMediatingModelingMyeloid-derived suppressor cellsNatural Killer CellsPathway interactionsPersonsPhysiologicalPlasmaPopulationPredispositionProcessProteinsPublishingRecombinantsRecoveryRegulatory T-LymphocyteRoleSerumStimulusTNF geneTNFRSF10A geneTNFRSF10B geneTestingTherapeuticViralViral PhysiologyWorkantiretroviral 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.
粒细胞髓源性抑制细胞(PMN-MDSC)的频率升高先于并有助于
艾滋病毒感染者(PLHIV)的免疫功能障碍。这种失调的潜在机制是
不太了解。正在研究的潜在机制包括PMN-MDSC影响CD 4 + T细胞
恢复,扩增T调节细胞(T-reg),诱导免疫检查点(IC),并抑制抗病毒抗体,
细胞毒性淋巴细胞的功能。虽然联合抗逆转录病毒治疗(cART)的开始可以减少
在PLHIV中,尽管有cART,PMN-MDSC水平仍可以保持升高,
cART不能补救所有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,
活化的人自然杀伤(NK)细胞和细胞毒性T淋巴细胞(CD 8 + T细胞,CTL)。TRAIL连接其
受体(也称为死亡受体(DR))诱导DR表达细胞的凋亡。PMN-MDSC表达
TRAIL-R1(DR 4)和2(DR 5)。最近发表的工作表明血清中的激动性可溶性抗体水平与血清中的激动性可溶性抗体水平之间存在联系。
TRAIL(sTRAIL)和PMN-MDSC在PLHIV中的频率。在HIV感染早期,PMN-MDSC频率呈反比
与血浆sTRAIL水平相关,重组TRAIL在体外诱导PMN-MDSC凋亡。因此,在本发明中,
DR连接,目前正在探索作为癌症的免疫疗法,可能是减少PMN-MDSC的一种方法
艾滋病毒感染者的频率。除TRAIL外,PMN-MDSC还表达NKG 2D配体。NKG 2D是NK细胞
激活受体和人CTL的阳性共刺激受体,NKG 2D配体表达使
PMN-MDSC对NK细胞杀伤高度敏感。然而,尽管有数据表明PMN-MDSC是必不可少的,
免疫功能障碍和HIV疾病的贡献者,靶向PLHIV中PMN-MDSC的方法还没有
被探索。使用具有胜任的和HIV易感的人源化免疫系统的小鼠模型,我们发现
PMN-MDSC在HIV感染后迅速扩增。与人类一样,PMN-MDSC与
该模型中的HIV病毒滴度和T-reg。细胞毒性淋巴细胞耗尽动物的机制研究显示
NK细胞和CTL可能控制PMN-MDSC扩增,表达NKG 2D,并上调PMN-MDSC的表达。
HIV感染后的TRAIL。我们建议探讨PMN-MDSC和随后的Treg
扩张受到控制。我们建议验证治疗性PMN-MDSC减少在治疗过程中的假设。
HIV感染可预防PMN-MDSC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NKG 2D通路对
控制PMN-MDSC和HIV感染后产生的Treg扩增。我们将探索治疗策略
以减少PMN-MDSC并防止体内HIV感染时的T-reg扩增。从我们获得的知识
这项工作将有助于对控制或加剧艾滋病毒感染诱导的免疫反应的机制有新的认识。
干扰和疾病。
项目成果
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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:
$ 3.54万 - 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:
$ 3.54万 - 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:
$ 3.54万 - 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:
10559918 - 财政年份:2022
- 资助金额:
$ 3.54万 - 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
- 资助金额:
$ 3.54万 - 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:
10374918 - 财政年份:2021
- 资助金额:
$ 3.54万 - 项目类别:
Mechanisms of Protection of Universal Therapeutic Antibodies to Influenza A
甲型流感通用治疗抗体的保护机制
- 批准号:
10078587 - 财政年份:2019
- 资助金额:
$ 3.54万 - 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:
$ 3.54万 - 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:
9204387 - 财政年份:2015
- 资助金额:
$ 3.54万 - 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:
9430685 - 财政年份:2015
- 资助金额:
$ 3.54万 - 项目类别: