The Cellular and Transcriptional Control of CD8 T Cell Functional Adaptation to Chronic Viruses

CD8 T 细胞功能适应慢性病毒的细胞和转录控制

基本信息

  • 批准号:
    9160163
  • 负责人:
  • 金额:
    $ 41.75万
  • 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:
    2016-05-16 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

Chronic viral infections such as HIV and HCV affecting millions of people globally are difficult to cure. Successful eradication of chronic viruses greatly depends on robust and long-lasting CD4 and CD8 T cell responses. Although virus-specific CD8 T cells gradually reduce their ability to produce effector cytokines and upregulate inhibitory receptor PD-1 in the face of persistent infection (commonly referred to as exhaustion), several studies, including the remarkable therapeutic effects achieved by PD-1 blockade, suggest that phenotypically “exhausted” T cells can mediate a crucial level of pathogen control. In contrast to the presently accepted view of progressive deterioration, we propose here that virus-specific CD8 T cells stably adjust their lineage specification and undergo a functional adaptation, which is optimized to fulfill a certain level of effector function and pathogen control without causing overwhelming immunopathology. This new concept is further supported by our preliminary data. We have recently found that novel cellular and signaling pathways, which connect CD4-derived IL-21 to BATF-IRF4-STAT3 regulated transcriptional machinery in CD8 T cells, vigorously promote the early-to-late phase developmental transition in virus-specific CD8 T cells. Based on these new findings, we hypothesize that elevated inflammatory cytokines (such as IL-21) and persistent antigen as hallmarks of chronic viral infection are tightly coupled through IL-21-STAT3-BATF and Antigen- TCR-IRF4 pathways, which converge on a transcriptional level to collaboratively regulate gene expression. Supporting this idea, our computational analyses have revealed that BATF and IRF4 cooperatively bind to the cis-regulatory elements of multiple genes associated with the late phase effector signatures. Intriguingly, many of these BATF-IRF4 compound-binding elements are adjacent to STAT3 binding sites, which provide the structural basis of BATF-dependent STAT3 binding and transcriptional activation as evidenced in our preliminary studies. Together, these lead us to propose a provocative model, in which BATF and IRF4 form a central regulatory hub to modulate chromatin accessibility and cooperate with STAT3 to regulate the central transcriptional networks that govern the late phase effector CD8 T cell differentiation and function. In this grant, we will use state-of-the-art techniques to elucidate (1) which subset of CD4 T cells provides “help” to sustain the effector function in CD8 T cells, (2) whether temporally regulated BATF expression and antigen dependent IRF4 expression are cooperatively required for CD8 effector T cell differentiation at the late phase of chronic infection, and (3) how BATF-IRF4 complex cooperates with JAK-STATs pathways on the epigenetic level to confer a distinct cell-fate specification in late effector CD8 T cells. Overall, this work will provide mechanistic insights into how CD8 T cells integrate the cellular, molecular and genetic signals to stably adjust their differentiation process to meet the needs of chronic infection. Ultimately, knowledge gained from this study could be harnessed to improve the effector function of CD8 T cells in treating chronic viruses and cancer.
影响全球数百万人的慢性病毒感染,如艾滋病毒和丙型肝炎病毒,很难治愈。 慢性病毒的成功根除在很大程度上取决于强大和持久的CD 4和CD 8 T细胞 应答尽管病毒特异性CD 8 T细胞逐渐降低其产生效应细胞因子的能力, 在面对持续感染时上调抑制性受体PD-1(通常称为衰竭), 一些研究,包括PD-1阻断所达到的显著治疗效果,表明, 表型上“耗尽”的T细胞可以介导关键水平的病原体控制。与目前相比, 我们在此提出,病毒特异性CD 8 T细胞稳定地调节其免疫功能, 谱系特化并经历功能适应,其被优化以满足一定水平的效应子。 功能和病原体控制,而不会引起压倒性的免疫病理学。这一新概念进一步 我们的初步数据支持。我们最近发现,新的细胞和信号通路, 将CD 4-衍生的IL-21连接到CD 8 T细胞中的BATF-IRF 4-STAT 3调节的转录机器, 有力地促进病毒特异性CD 8 T细胞从早期到晚期的发育转变。基于 这些新的发现,我们假设升高的炎症细胞因子(如IL-21)和持续的 作为慢性病毒感染标志的抗原通过IL-21-STAT 3-BATF和抗原- TCR-IRF 4通路,其在转录水平上会聚以协同调节基因表达。 支持这一观点,我们的计算分析显示,BATF和IRF 4协同结合到 与晚期效应物标签相关的多个基因的顺式调节元件。有趣的是,许多 这些BATF-IRF 4化合物结合元件中的至少一个与STAT 3结合位点相邻,所述STAT 3结合位点提供了与所述化合物结合的结合位点。 BATF依赖性STAT 3结合和转录激活的结构基础,如我们在 初步研究。总之,这些导致我们提出一个挑衅性的模型,其中BATF和IRF 4形成一个 调节染色质可及性的中央调节枢纽,并与STAT 3合作调节中央调节中心, 这些转录网络控制晚期效应CD 8 T细胞分化和功能。在这份补助金中, 我们将使用最先进的技术来阐明(1)CD 4 T细胞的哪一个亚群提供“帮助”维持 CD 8 T细胞中的效应子功能,(2)是否暂时调节BATF表达和抗原依赖性 IRF 4表达是慢性淋巴细胞白血病晚期CD 8效应T细胞分化所需的协同作用。 感染,以及(3)BATF-IRF 4复合物如何在表观遗传水平上与JAK-STAT通路合作, 在晚期效应CD 8 T细胞中赋予不同的细胞命运特化。总的来说,这项工作将提供机械 深入了解CD 8 T细胞如何整合细胞,分子和遗传信号,以稳定地调节其 分化过程,以满足慢性感染的需要。最终,从这项研究中获得的知识 可以用来改善CD 8 T细胞在治疗慢性病毒和癌症中的效应功能。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

WEIGUO CUI其他文献

WEIGUO CUI的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('WEIGUO CUI', 18)}}的其他基金

Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10743327
  • 财政年份:
    2022
  • 资助金额:
    $ 41.75万
  • 项目类别:
Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages
Pim1 激酶协调 PPAR gamma 通路和线粒体功能,介导巨噬细胞中的促动脉粥样硬化反应
  • 批准号:
    10209655
  • 财政年份:
    2021
  • 资助金额:
    $ 41.75万
  • 项目类别:
Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages
Pim1 激酶协调 PPAR gamma 通路和线粒体功能,介导巨噬细胞中的促动脉粥样硬化反应
  • 批准号:
    10591599
  • 财政年份:
    2021
  • 资助金额:
    $ 41.75万
  • 项目类别:
The cellular mechanisms of immunological memory development in COVID-19 patients
COVID-19患者免疫记忆发展的细胞机制
  • 批准号:
    10745497
  • 财政年份:
    2021
  • 资助金额:
    $ 41.75万
  • 项目类别:
Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages
Pim1 激酶协调 PPAR gamma 通路和线粒体功能,介导巨噬细胞中的促动脉粥样硬化反应
  • 批准号:
    10372226
  • 财政年份:
    2021
  • 资助金额:
    $ 41.75万
  • 项目类别:
The cellular mechanisms of immunological memory development in COVID-19 patients
COVID-19患者免疫记忆发展的细胞机制
  • 批准号:
    10465343
  • 财政年份:
    2021
  • 资助金额:
    $ 41.75万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10721409
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10536743
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10428867
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10311054
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:

相似海外基金

How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
  • 批准号:
    2315783
  • 财政年份:
    2023
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
  • 批准号:
    2719534
  • 财政年份:
    2022
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633211
  • 财政年份:
    2020
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
  • 批准号:
    20K01113
  • 财政年份:
    2020
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2436895
  • 财政年份:
    2020
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633207
  • 财政年份:
    2020
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
  • 批准号:
    426559561
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
  • 批准号:
    2236701
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
  • 批准号:
    19K01745
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
  • 批准号:
    415543446
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
    Research Fellowships
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了