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
- 来源:
- 关键词:Antigen-Presenting CellsAntigensAntitumor ResponseCD4 Positive T LymphocytesCD40 LigandCD8-Positive T-LymphocytesCD8B1 geneCardiolipinsCell CommunicationCellsCross PresentationDataDendritic CellsDevelopmentEnhancersGenesHelper-Inducer T-LymphocyteIndividualKnowledgeLicensingLigandsLipidsMethodsModelingMusNaturePathway interactionsProcessPublishingRoleSideSignal TransductionSourceT cell responseT-Cell ReceptorT-LymphocyteTNFRSF5 geneTNFSF5 geneTestingTimeTransgenic OrganismsTumor ImmunityTumor-DerivedVirusWorkarmbasecell typein vivoneoantigensnew therapeutic targetnovelpathogenprogramsresponsetranscription factortumorγδ T cells
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
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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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
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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
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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
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