Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity
Tcf1 编程 CD8 T 细胞反应以增强病毒和癌症免疫力
基本信息
- 批准号:10396568
- 负责人:
- 金额:$ 52.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAcuteAffectAntigensBLR1 geneCD8-Positive T-LymphocytesCD8B1 geneCell CycleCellsChromatinChromatin LoopChronicCommunicable DiseasesDNase I hypersensitive sites sequencingDissectionEctopic ExpressionEnhancersEnvironmentEpigenetic ProcessExhibitsFunctional disorderFundingGenerationsGenetic TranscriptionGenomeGlycolysis InductionGlycolysis PathwayGoalsHi-CHistone DeacetylaseImmune responseImpairmentInfectionKnowledgeLinkMalignant - descriptorMalignant NeoplasmsMature T-LymphocyteMemoryModelingModificationMolecularNatureOutputPathogenicityPathway interactionsPhasePhenotypePreventive vaccineProgress ReportsResearchRestRoleSELL geneSystems BiologyT cell differentiationT cell responseT cell transcription factor 1T memory cellT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticThymocyte DevelopmentTimeTranscriptional RegulationTumor ImmunityVaccinesViralViral CancerVirus Diseasesacute infectionantigen challengebasecancer immunotherapycell transformationchronic infectioncofactorcytotoxiccytotoxic CD8 T cellsexhaustexhaustionfunctional restorationgain of functionimmune checkpoint blockadeimprovedinsightneoplastic cellpathogenpre-clinicalprogramspromoterresponseself-renewalstemstem cellsstem-like cellsuccesstranscription factortranscriptometranscriptomicstumor
项目摘要
CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against
pathogens and malignantly transformed cells. Depending on the nature of antigen challenge, CD8+ T cells are
equipped with certain levels of plasticity to maximize reduction of infected or tumor cells. After pathogen
clearance resulting from acute infections, memory CD8+ T cells persist for long term and provide enhanced
protection against the same or related pathogens, and these features constitute the basis for prophylactic
vaccines. On the other hand, antigen persistence, as a result of chronic infection and cancers, causes CD8+ T
cell exhaustion or dysfunction; nonetheless, the exhausted CD8+ T (Tex) cells can be partly reinvigorated, as
seen in recent success of checkpoint blockade in cancer immunotherapy.
Understanding molecular circuits that underlie T cell memory and exhaustion is critical for fully harnessing the
potentials of cytotoxic CD8+ T cells for improving viral or cancer immunity. In this competitive renewal
application, our goal is to uncover the uncharted links of Tcf1 and its HDAC activity with chromatin accessibility
and chromatin looping-based enhancer-promoter interactions in memory and exhausted CD8+ T cells. The
specific aims are as follows:
Aim 1. To investigate how Tcf1 preprograms enhanced recall responses by memory CD8+ T cells.
Memory CD8+ T cells exhibit enhanced recall response by more robust proliferation and more rapid activation
of cytolytic activities than naïve T cells. A major knowledge gap remains regarding the molecular basis and
molecular regulators that underlie the heightened immune response. We hypothesize that Tcf1 preprograms
central memory CD8+ T cells for their enhanced responsiveness to recall stimulation. We will use unbiased
systems biology approaches including DNase-seq and HiC to define how Tcf1 and its HDAC activity control
chromatin accessibility and looping. Combined with comprehensive functional studies, we will perform in-depth
dissection of the unique molecular wiring that dictates enhanced recall responses by Tcm cells.
Aim 2. To determine the capacity of Tcf1 to enhance functional restoration of exhausted CD8+ T cells.
Recent advances revealed that Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has
stem cell-like self-renewing capacity and expresses an elevated level of Tcf1. We hypothesize that Tcf1-
dependent regulatory circuits can be utilized to durably enhance Tex functional restoration. We will test various
Tcf1 forms and cofactor combinations in chronic viral infection and tumor models, and determine their impact
on chromatin accessibility/looping and its link to favorable functional output by Tex cells.
This proposal will mechanistically elucidate how Tcf1 orchestrates 3D-genome to program memory CD8+ and
exhausted CD8+ T cells for enhanced functional output, and provide timely, much needed insights into devising
more effective vaccines and therapeutics for infectious diseases and cancers.
CD8+ T淋巴细胞在建立保护性细胞免疫反应中起着至关重要的作用
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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{{ truncateString('Hai-Hui Xue', 18)}}的其他基金
Modulating costimulation pathways to improve follicular helper T cell and antibody responses
调节共刺激途径以改善滤泡辅助 T 细胞和抗体反应
- 批准号:
10571687 - 财政年份:2022
- 资助金额:
$ 52.27万 - 项目类别:
Modulating costimulation pathways to improve follicular helper T cell and antibody responses
调节共刺激途径以改善滤泡辅助 T 细胞和抗体反应
- 批准号:
10367461 - 财政年份:2022
- 资助金额:
$ 52.27万 - 项目类别:
Targeting Tcf/Lef-transcriptional program in leukemic stem cells
靶向白血病干细胞中的 Tcf/Lef 转录程序
- 批准号:
10163369 - 财政年份:2016
- 资助金额:
$ 52.27万 - 项目类别:
Targeting Tcf/Lef-transcriptional program in leukemic stem cells
靶向白血病干细胞中的 Tcf/Lef 转录程序
- 批准号:
9212638 - 财政年份:2016
- 资助金额:
$ 52.27万 - 项目类别:
Targeting Tcf/Lef-transcriptional program in leukemic stem cells
靶向白血病干细胞中的 Tcf/Lef 转录程序
- 批准号:
9022091 - 财政年份:2016
- 资助金额:
$ 52.27万 - 项目类别:
Tcf/Lef-b-catenin in T cell identity and cancer
Tcf/Lef-b-连环蛋白在 T 细胞身份和癌症中的作用
- 批准号:
9208107 - 财政年份:2015
- 资助金额:
$ 52.27万 - 项目类别:
Tcf/Lef-b-catenin in T cell identity and cancer
Tcf/Lef-b-连环蛋白在 T 细胞身份和癌症中的作用
- 批准号:
8883981 - 财政年份:2015
- 资助金额:
$ 52.27万 - 项目类别:
Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity
Tcf1 编程 CD8 T 细胞反应以增强病毒和癌症免疫力
- 批准号:
10611882 - 财政年份:2015
- 资助金额:
$ 52.27万 - 项目类别:
Decoding TCF1-controlled transcriptional program that promotes memory T cell fate
解码 TCF1 控制的转录程序,促进记忆 T 细胞的命运
- 批准号:
8487767 - 财政年份:2013
- 资助金额:
$ 52.27万 - 项目类别:
Decoding TCF1-controlled transcriptional program that promotes memory T cell fate
解码 TCF1 控制的转录程序,促进记忆 T 细胞的命运
- 批准号:
8650791 - 财政年份:2013
- 资助金额:
$ 52.27万 - 项目类别:
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