Antigen export in M. tuberculosis evasion of CD4 T cells
结核分枝杆菌逃避 CD4 T 细胞的抗原输出
基本信息
- 批准号:9318402
- 负责人:
- 金额:$ 72.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-20 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntigen PresentationAntigen Presentation PathwayAntigen TargetingAntigensAntimycobacterial AgentsAttenuatedAutophagocytosisBacteriaBacterial AntigensBypassCD4 Positive T LymphocytesCell membraneCellsClinical TrialsDataDendritic CellsDevelopmentDisease ProgressionDynaminEffectivenessExtracellular SpaceGenerationsGenus MycobacteriumGoalsHistocompatibility Antigens Class IIImmune systemImmunodominant AntigensImpairmentInfectionInfection ControlKinesinLungManuscriptsMeasuresMediator of activation proteinMembraneMicrobeMicrotubulesMolecularMolecular MotorsMycobacterium tuberculosisPathway interactionsPhagosomesPharmaceutical PreparationsPharmacologyPhaseProblem SolvingProteinsPublicationsReportingRoleSecondary toShunt DeviceSiteT cell responseT-LymphocyteTestingTimeTuberculosisTuberculosis VaccinesVaccinationVaccine DesignVaccinesVesicleVesicle Transport PathwayWorkadaptive immunityimprovedin vivolymph nodesmacrophagenovelpathogenpreventresponsevaccine development
项目摘要
A major obstacle to developing an efficacious TB vaccine is illustrated by the results of a recent clinical trial in
which the vaccine induced polyfunctional T cell responses, yet it did not prevent TB. This obstacle is also
illustrated in animal models, as existing TB vaccines induce T cell responses, but have only modest effects on
bacterial burdens. These results suggest that antigen-specific T cells are generated by infection or vaccination
and they can be activated by ex vivo restimulation, but they are not activated effectively at the site of infection.
The long term objective of this project is to guide development of efficacious TB vaccines by: 1) characterizing
a major mechanism that limits the ability of antigen-specific CD4 T cells to recognize M. tuberculosis-infected
cells and become activated at the site of infection; and 2) developing solutions that overcome or bypass that
mechanism. We have discovered that M. tuberculosis-infected cells activate CD4 T cells poorly because
multiple secreted bacterial antigens are shunted away from the MHC class II antigen processing and
presentation pathway and are exported from the infected cells. This novel mechanism, which we term antigen
export, involves intracellular vesicular transport, and requires the microtubule-directed molecular motor,
kinesin-2. When we deplete M. tuberculosis-infected cells of kinesin 2 and thus block antigen export, we find
increased MHC class II antigen presentation and CD4 T cell activation by infected cells, resulting in improved
control of intracellular M. tuberculosis. This indicates that CD4 T cells have the potential to exert effective
antimycobacterial activity, but their activation is limited by poor antigen presentation by infected cells, and poor
antigen presentation is secondary to antigen export. This project will extend these findings and characterize
the other cellular mechanisms required for antigen export, including budding of antigen export vesicles (AEV)
from phagosomes, intracellular targeting of AEV, and fusion of AEV membranes with the plasma membrane for
release of antigens to the extracellular space. Our goal is to identify host molecules that can be targeted with
drugs to block antigen export and make antigen-specific CD4 T cells more effective in TB. To inform TB
vaccine design, we hypothesize that nonsecreted (and nonexported) antigens are more desirable than
secreted antigens in TB vaccines, since secreted antigens are exported from infected cells, making the
infected cells poor targets for recognition by CD4 T cells specific for those antigens. To test the hypothesis that
CD4 T cells directed against a nonsecreted antigen are more efficacious than those directed against a
secreted antigen, we have modified an immunodominant secreted M. tuberculosis antigen (Ag85B) so that it is
not secreted, and we will determine whether bacteria that express nonsecreted-nonexported Ag85B are better
controlled by CD4 T cells in vivo. Together, our proposed studies will guide efforts to make naturally-occurring
and vaccine-induced CD4 T cells more effective in TB, and contribute to solving the problem of global
tuberculosis.
最近一项临床试验的结果表明,开发有效的结核病疫苗的一个主要障碍是
其中疫苗诱导了多功能T细胞反应,但它并没有预防结核病。这一障碍也是
在动物模型中显示,因为现有的结核病疫苗诱导T细胞反应,但对
细菌的负担。这些结果表明,抗原特异性T细胞是由感染或接种疫苗产生的
它们可以通过体外再刺激激活,但在感染部位不能有效激活。
该项目的长期目标是通过以下方式指导有效结核病疫苗的开发:1)表征
限制抗原特异性CD4T细胞识别结核分枝杆菌感染能力的主要机制
细胞并在感染部位被激活;以及2)开发克服或绕过这一点的解决方案
机制。我们发现,结核分枝杆菌感染细胞对CD4T细胞的激活能力很差,原因是
多个分泌的细菌抗原从MHC II类抗原加工中分流出来
呈现途径,并从感染细胞输出。这种新的机制,我们称之为抗原
出口,涉及细胞内的囊泡运输,需要微管导向的分子马达,
激动素-2。当我们耗尽结核分枝杆菌感染细胞的激动素2,从而阻止抗原输出时,我们发现
感染细胞增加MHC II类抗原提呈和CD4T细胞激活,导致改善
胞内结核分枝杆菌的控制。这表明CD4T细胞具有发挥有效作用的潜力。
抗分枝杆菌活性,但它们的活性受到感染细胞抗原提呈差的限制,而且
抗原呈递是次要的抗原输出。该项目将扩展这些发现并描述
抗原输出所需的其他细胞机制,包括抗原输出小泡(AEV)的萌发
来自吞噬小体,AEV的细胞内靶向,AEV膜与质膜的融合
将抗原释放到细胞外空间。我们的目标是确定可以作为靶点的宿主分子
阻止抗原输出并使抗原特异性的CD4T细胞在结核病中更有效的药物。通知结核病
疫苗设计,我们假设非分泌(和非输出)抗原比
结核疫苗中的分泌性抗原,因为分泌性抗原是从受感染的细胞输出的,使
被感染的细胞很难被针对这些抗原的CD4T细胞识别。来检验这一假设
针对非分泌性抗原的CD4T细胞比针对非分泌性抗原的CD4T细胞更有效
分泌型抗原,我们对免疫优势分泌型结核分枝杆菌抗原(Ag85B)进行了修饰,使其成为
不分泌,我们将确定表达非分泌-非出口Ag85B的细菌是否更好
体内受CD4T细胞控制。总之,我们提议的研究将指导人们努力使自然发生
而疫苗诱导的CD4T细胞在结核病中更有效,并有助于解决全球性的
肺结核。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Joel D. Ernst其他文献
The immunological life cycle of tuberculosis
结核病的免疫生命周期
- DOI:
10.1038/nri3259 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:60.900
- 作者:
Joel D. Ernst - 通讯作者:
Joel D. Ernst
Transfer of phagocytosed particles to the parasitophorous vacuole of Leishmania mexicana is a transient phenomenon preceding the acquisition of annexin I by the phagosome.
吞噬颗粒向墨西哥利什曼原虫寄生液泡的转移是吞噬体获得膜联蛋白 I 之前的短暂现象。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:4
- 作者:
Helen L. Collins;Ulrich E. Schaible;Joel D. Ernst;David G. Russell - 通讯作者:
David G. Russell
Editorial response: variation in clinical and immune responses to bacille Calmette-Guérin--implications for an improved tuberculosis vaccine.
编辑回应:卡介苗临床和免疫反应的变化——对改进结核病疫苗的影响。
- DOI:
10.1086/515202 - 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Joel D. Ernst - 通讯作者:
Joel D. Ernst
Antibody-Fab and -Fc features promote emMycobacterium tuberculosis/em restriction
抗体的 Fab 和 Fc 特征促进了对结核分枝杆菌的限制。
- DOI:
10.1016/j.immuni.2025.05.004 - 发表时间:
2025-06-10 - 期刊:
- 影响因子:26.300
- 作者:
Patricia S. Grace;Joshua M. Peters;Jaimie Sixsmith;Richard Lu;Edward B. Irvine;Corinne Luedeman;Brooke A. Fenderson;Andrew Vickers;Matthew D. Slein;Tanya McKitrick;Mo-Hui Wei;Richard D. Cummings;Aaron Wallace;Lisa A. Cavacini;Alok Choudhary;Megan K. Proulx;Christopher Sundling;Gunilla Källenius;Rajko Reljic;Joel D. Ernst;Galit Alter - 通讯作者:
Galit Alter
Finding and filling the knowledge gaps in mechanisms of T cell-mediated TB immunity to inform vaccine design
寻找并填补 T 细胞介导的结核病免疫机制中的知识空白,为疫苗设计提供信息
- DOI:
10.1038/s41577-025-01192-z - 发表时间:
2025-06-13 - 期刊:
- 影响因子:60.900
- 作者:
Emma Lefrançais;Denis Hudrisier;Olivier Neyrolles;Samuel M. Behar;Joel D. Ernst - 通讯作者:
Joel D. Ernst
Joel D. Ernst的其他文献
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{{ truncateString('Joel D. Ernst', 18)}}的其他基金
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
- 批准号:
10735075 - 财政年份:2023
- 资助金额:
$ 72.01万 - 项目类别:
Functional dynamics of TB granuloma architecture
结核肉芽肿结构的功能动力学
- 批准号:
10593978 - 财政年份:2022
- 资助金额:
$ 72.01万 - 项目类别:
Functional dynamics of TB granuloma architecture
结核肉芽肿结构的功能动力学
- 批准号:
10358264 - 财政年份:2022
- 资助金额:
$ 72.01万 - 项目类别:
Host genetic diversity, mononuclear phagocytes, and outcomes of TB
宿主遗传多样性、单核吞噬细胞和结核病的结果
- 批准号:
10005738 - 财政年份:2020
- 资助金额:
$ 72.01万 - 项目类别:
Host genetic diversity, mononuclear phagocytes, and outcomes of TB
宿主遗传多样性、单核吞噬细胞和结核病的结果
- 批准号:
10194362 - 财政年份:2020
- 资助金额:
$ 72.01万 - 项目类别:
Epitope-specific T cell activation to complement TB immunity and vaccine efficacy
表位特异性 T 细胞激活可补充结核病免疫和疫苗功效
- 批准号:
8867688 - 财政年份:2014
- 资助金额:
$ 72.01万 - 项目类别:
Initiation of the Immune Response to M. tuberculosis
对结核分枝杆菌的免疫反应的启动
- 批准号:
8678398 - 财政年份:2014
- 资助金额:
$ 72.01万 - 项目类别:
Mycobacterium tuberculosis evasion of CD4+ T cells in vivo
体内结核分枝杆菌逃避 CD4 T 细胞
- 批准号:
8678383 - 财政年份:2013
- 资助金额:
$ 72.01万 - 项目类别:
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