Understanding the Mechanisms of DC Licensing in CD8 T Cell Priming

了解 CD8 T 细胞启动中 DC 许可的机制

基本信息

  • 批准号:
    10211694
  • 负责人:
  • 金额:
    $ 47.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Effective responses to viruses, intracellular pathogens and tumors rely on the successful expansion and arming of cytolytic CD8 T cells from a naïve and quiescent T cell repertoire. This process, called CD8 T cell priming, is dependent on a specialized antigen-presenting cell known as conventional dendritic cells (cDCs). Recent studies from our lab have shown that a specific type of dendritic cells, called cDC1, is responsible for CD8 T cell priming and depends on the transcription factor Batf3 for development. In the process of priming CD8 T cells, the cDC1 captures foreign antigens or tumor-specific neo-antigens, and presents these antigens on the MHC-I molecule in order to stimulate the T cell receptor (TCR) of the CD8 T cell. In the absence of cDC1, such as in Batf3-deficient mice, CD8 T cells are not activated against viruses or tumors. In addition, however, full activation of CD8 T cell requires that cDC1 receive signals that program its ability to fully activate CD8 T cells. This process is called `DC licensing', but is currently not fully characterized. Our recent work has shown that current models for DC licensing are incomplete. Specifically, while we have confirmed the requirement for CD40 signaling in response to CD40L provided by a helper cell, we have shown that the expected target of CD40, CD70, does not explain the beneficial effect of DC licensing for tumor rejection. This result implies that additional targets of CD40 are needed to understand DC licensing. Further, it has been thought that CD4 T cells are the exclusive agent in the licensing process. However, these conclusions derived from older studies and less precise methods. In contrast, we developed an Xcr1-Cre deletor strain to delete genes specifically from cDC1, and found unexpected results, that CD4 T cells are not always critical for cDC1 licensing, suggesting that other cells expressing CD40L may be involved. Further, mechanism by which CD40 signaling induces licensing of the cDC1 is unclear. Several mechanisms have been proposed, but our preliminary data excludes the major proposed mechanism, those invoking CD70, as being critical for the effect of licensed cDC1 in priming CD8 T cells. Our proposal will first test (Aim 1) which Batf3-specific genes expressed in cDC1 are important for cDC1 to support CD8 T cells responses. Second (Aim 2), we will determine identify the targets of CD40 signaling in cDC1 that are required for fully activating CD8 T cells. Finally, in Aim 3, we will test the role of cells that we have identified as alternative sources of CD40 ligand, including iNKT cells and γδ T cells.
摘要 对病毒、细胞内病原体和肿瘤的有效反应依赖于从幼稚和静止的T细胞库中成功地扩增和武装具有细胞毒性的CD8T细胞。这一过程被称为CD8T细胞启动,依赖于一种特殊的抗原提呈细胞,称为常规树突状细胞(CDCs)。我们实验室最近的研究表明,一种特殊类型的树突状细胞,称为cDc1,负责CD8 T细胞的启动和依赖转录因子BATF3的发育。在启动CD8 T细胞的过程中 细胞,cDC1捕获外来抗原或肿瘤特异性新抗原,并将这些抗原呈现在 MHC-I分子,以刺激CD8T细胞的T细胞受体(TCR)。在没有cdc1的情况下, 与BATF3基因缺陷的小鼠一样,CD8T细胞不会被病毒或肿瘤激活。然而,除此之外,完整的 CD8T细胞的激活需要cDC1接收信号来编程其完全激活CD8T细胞的能力。 这一过程被称为“DC许可”,但目前还没有完全确定其特征。我们最近的研究表明, 目前的DC许可模式是不完整的。具体地说,虽然我们已经确认了 CD40信号响应辅助细胞提供的CD40L,我们已经证明了预期的靶点 CD40、CD70不能解释DC许可对肿瘤排斥的有益效果。这一结果意味着 要理解DC许可,还需要CD40的其他目标。此外,人们还认为CD4T CELL是许可过程中的独家代理。然而,这些结论来自于较早的研究 以及不太精确的方法。相反,我们开发了一种Xcr1-Cre缺失菌株来特异性地删除基因 结果发现,CD4T细胞并不总是对cDC1的许可至关重要,这表明表达CD40L的其他细胞可能参与了这一过程。此外,CD40信号诱导的机制 CDC1的许可尚不清楚。已经提出了几种机制,但我们的初步数据排除了 主要建议的机制,即那些调用CD70的机制,对于授权的CDC1在启动CD8T细胞方面的效果至关重要。我们的建议将首先测试(目标1)哪些BATF3特异性基因在cDC1中表达是重要的 以支持CD8 T细胞反应。第二个(目标2),我们将确定CD40的靶点 CD8T细胞完全激活所需的CDC1中的信号。最后,在目标3中,我们将测试细胞的作用 我们已经确定CD40L的替代来源,包括iNKT细胞和γδT细胞。

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 }}

Kenneth M Murphy其他文献

Competition for cytokines: Treg cells take all
细胞因子的竞争:调节性 T 细胞独占鳌头
  • DOI:
    10.1038/ni1207-1285
  • 发表时间:
    2007-12-01
  • 期刊:
  • 影响因子:
    27.600
  • 作者:
    Alexander Scheffold;Kenneth M Murphy;Thomas Höfer
  • 通讯作者:
    Thomas Höfer
Recent progress in type 1 classical dendritic cell cross-presentation - cytosolic, vacuolar, or both?
  • DOI:
    10.1016/j.coi.2023.102350
  • 发表时间:
    2023-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Ray A Ohara;Kenneth M Murphy
  • 通讯作者:
    Kenneth M Murphy

Kenneth M Murphy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('Kenneth M Murphy', 18)}}的其他基金

Transcriptional basis of embryonic macrophage development
胚胎巨噬细胞发育的转录基础
  • 批准号:
    10531441
  • 财政年份:
    2022
  • 资助金额:
    $ 47.76万
  • 项目类别:
Molecular Basis of cDC1 Development
cDC1 开发的分子基础
  • 批准号:
    10450553
  • 财政年份:
    2022
  • 资助金额:
    $ 47.76万
  • 项目类别:
Molecular Basis of cDC1 Development
cDC1 开发的分子基础
  • 批准号:
    10649736
  • 财政年份:
    2022
  • 资助金额:
    $ 47.76万
  • 项目类别:
Transcriptional basis of embryonic macrophage development
胚胎巨噬细胞发育的转录基础
  • 批准号:
    10654858
  • 财政年份:
    2022
  • 资助金额:
    $ 47.76万
  • 项目类别:
Understanding the Mechanisms of DC Licensing in CD8 T Cell Priming
了解 CD8 T 细胞启动中 DC 许可的机制
  • 批准号:
    10411993
  • 财政年份:
    2021
  • 资助金额:
    $ 47.76万
  • 项目类别:
Mechanism of c-MYC repression by IRF8 in myeloid lineages
IRF8 在骨髓谱系中抑制 c-MYC 的机制
  • 批准号:
    10379675
  • 财政年份:
    2021
  • 资助金额:
    $ 47.76万
  • 项目类别:
Understanding the Mechanisms of DC Licensing in CD8 T Cell Priming
了解 CD8 T 细胞启动中 DC 许可的机制
  • 批准号:
    10630938
  • 财政年份:
    2021
  • 资助金额:
    $ 47.76万
  • 项目类别:
Mechanism of c-MYC repression by IRF8 in myeloid lineages
IRF8 在骨髓谱系中抑制 c-MYC 的机制
  • 批准号:
    10493389
  • 财政年份:
    2021
  • 资助金额:
    $ 47.76万
  • 项目类别:
Function of Wdfy4 in cross-presentation and immunity
Wdfy4在交叉呈递和免疫中的功能
  • 批准号:
    10203752
  • 财政年份:
    2019
  • 资助金额:
    $ 47.76万
  • 项目类别:
Function of Wdfy4 in cross-presentation and immunity
Wdfy4在交叉呈递和免疫中的功能
  • 批准号:
    10430144
  • 财政年份:
    2019
  • 资助金额:
    $ 47.76万
  • 项目类别:

相似国自然基金

Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
  • 批准号:
    30801055
  • 批准年份:
    2008
  • 资助金额:
    19.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs
牛疱疹病毒 4 作为猪非洲猪瘟病毒抗原的疫苗平台
  • 批准号:
    BB/Y006224/1
  • 财政年份:
    2024
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Research Grant
Uncovering tumor specific antigens and vulnerabilities in ETP-acute lymphoblastic leukemia
揭示 ETP-急性淋巴细胞白血病的肿瘤特异性抗原和脆弱性
  • 批准号:
    480030
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Operating Grants
A novel vaccine approach combining mosquito salivary antigens and viral antigens to protect against Zika, chikungunya and other arboviral infections.
一种结合蚊子唾液抗原和病毒抗原的新型疫苗方法,可预防寨卡病毒、基孔肯雅热和其他虫媒病毒感染。
  • 批准号:
    10083718
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Small Business Research Initiative
Regulation of B cell responses to vaccines by long-term retention of antigens in germinal centres
通过在生发中心长期保留抗原来调节 B 细胞对疫苗的反应
  • 批准号:
    MR/X009254/1
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Research Grant
Adaptive Discrimination of Risk of Antigens in Immune Memory Dynamics
免疫记忆动态中抗原风险的适应性辨别
  • 批准号:
    22KJ1758
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
22-ICRAD Call 2 - Improving the diagnosis of tuberculosis in domestic ruminants through the use of new antigens and test platforms
22-ICRAD 呼吁 2 - 通过使用新抗原和测试平台改善家养反刍动物结核病的诊断
  • 批准号:
    BB/Y000927/1
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Research Grant
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
  • 批准号:
    10795212
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
Integrative proteome analysis to harness humoral immune response against tumor antigens
综合蛋白质组分析利用针对肿瘤抗原的体液免疫反应
  • 批准号:
    23K18249
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
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:
    $ 47.76万
  • 项目类别:
Targeting T3SA proteins as protective antigens against Yersinia
将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原
  • 批准号:
    10645989
  • 财政年份:
    2023
  • 资助金额:
    $ 47.76万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了