Molecular Basis of cDC1 Development
cDC1 开发的分子基础
基本信息
- 批准号:10649736
- 负责人:
- 金额:$ 55.99万
- 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:2022-06-17 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAblationAddressAntigen-Presenting CellsAntigensBindingBypassCCAAT-Enhancer-Binding ProteinsCD8-Positive T-LymphocytesCRISPR/Cas technologyCell physiologyCell surfaceCellsChIP-seqChimeric ProteinsClinicalComplexCritiquesCross PresentationDataDendritic CellsDependenceDevelopmentElementsEnhancersEpitopesExhibitsFLT3 geneFLT3 ligandFamily memberGene TargetingGenerationsGenesGeneticGenetic TranscriptionGoalsHomeostasisHumanImmune responseImmunityIn VitroInfectionLiteratureLymphoid TissueMHC antigenMacrophageMethodsMolecularMusMyelogenousMyeloid CellsOutputPathway interactionsPeptide Initiation FactorsPeptidesPopulationProcessProductionProteinsPublishingReagentReporterReportingRepressionRoleRouteSignal InductionSignal TransductionSiteSpecific qualifier valueSuggestionSystemT cell responseT-Cell ActivationTestingTherapeuticTimeTumor-DerivedVaccinesViralVirusWorkadaptive immune responsedesigneffector T cellgranulocytein vivointerestmonocytenovelprogenitorresponsestem cellstooltranscription factortumoruptake
项目摘要
ABSTRACT
The initial adaptive immune response to tumors and many viruses relies on the priming of CD8 T cells to gen-
erate cytolytic effector T cells that can specifically target tumors or virally infected cells. The priming of CD8 T
cells to these agents is carried out in vivo by a particular type of antigen presenting cell that is a component of
the myeloid system and a member of the family of dendritic cells. Classical dendritic cells (cDCs) comprise
several closely related lineages that are clearly distinct from other myeloid cells such as macrophages, mono-
cytes or granulocytes. Primarily, cDCs serve to activate T cells against infections in the central lymphoid tis-
sues, rather than carrying out direct effector functions at sites of infections as the other myeloid lineages do.
The cDCs are themselves comprised of at least two major branches, now called cDC1 and cDC2. The cDC1
is a lineage that specializes in the uptake and processing of cell-associated antigens, such as from tumors of
virally infected cells and the expression of peptide epitopes on its cell surface in conjunction with MHC-I mole-
cules. This form of antigen:MHC-I complex is able to activate CD8 T cells, and not CD4 T cells. This process is
called cross-presentation. The cDC2 is not capable of carrying out cross-presentation to viruses or tumors in
vivo. The cDC1 has many genetic and molecular differences from cDC2; cDC1 require a distinct set of tran-
scription factors for their development that are not required for cDC2. This includes dependence on the tran-
scription factors Nfil3, Id2, Irf8 and Batf3. Our recent work showed that the genetic hierarchy among these fac-
tors has Nfil3 as the first and initiating factor, acting to indirectly induce Id2 and Batf3 via the suppression of the
repressor Zeb2. However, it is still unknown how Nfil3 is induced to initiate this process, and how Nfil3 works to
suppress Zeb2 expression. It has recently become important to understand these details because of the clini-
cal interest to apply Flt3L administration as a therapeutic in expanding the in vivo population of cDC1. It has
been known for some time that Fl3L can expand dendritic cells in general and expand cDC1 in particular. But
we have uncovered a surprising and worrisome fact; Flt3L administration will expand cDC1-like cells even in
Nfil3-deficient mice, which completely lack cDC1 beforehand. The expansion of cDC1 in Nfil3-deficent mice
produced by Flt3L is of the same magnitude as the expansion in WT mice. Thus, Flt3L is inducing cDC1 by a
different genetic route than normal cDC1 development. There has been no test of whether such cDC1 cells
function normally and will boost an immune response. This application will systematically address this issue by
Aim 1) defining the normal process by which Nfil3 is induced, Aim 2) define the mechanism by which NFIL3
drives cDC1 development, and Aim 3) determine whether Flt3-induced cDC1 function normally and determine
the mechanism by which Flt3L bypasses the normal requirement for Nfil3 in cDC1 development.
摘要
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)
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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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{{ 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:
$ 55.99万 - 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:
$ 55.99万 - 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:
10211694 - 财政年份:2021
- 资助金额:
$ 55.99万 - 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:
$ 55.99万 - 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:
$ 55.99万 - 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:
$ 55.99万 - 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:
$ 55.99万 - 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:
$ 55.99万 - 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:
$ 55.99万 - 项目类别:
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