Defining the regulation and regulatory mechanisms of TCF-1 in CD8+ T cell differentiation
明确TCF-1在CD8 T细胞分化中的调节和调控机制
基本信息
- 批准号:10605014
- 负责人:
- 金额:$ 3.36万
- 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:2022-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAffinityAlpha Interleukin 2 ReceptorAntigensAttenuatedBindingBiological AssayCD8-Positive T-LymphocytesCellsCessation of lifeChromatinChronicClonal ExpansionComplementCuesCytokine ReceptorsDecision MakingDependenceDevelopmentDown-RegulationEffector CellElementsEngineeringEpigenetic ProcessFamilyGene Expression ProfileGene Expression RegulationGenesGenetic TranscriptionGoalsHistone DeacetylaseIL2RA geneIRF4 geneImmune responseImmunityImmunologic SurveillanceImmunotherapeutic agentImmunotherapyInfectionInflammatoryInterleukin 2 ReceptorInterleukin-12Interleukin-15Interleukin-2KnowledgeLymphocytic choriomeningitis virusMalignant NeoplasmsMediatingMemoryModelingMolecularMusMutatePhenotypePopulationReceptor SignalingRecruitment ActivityRegulationRegulatory ElementRepressionResearch Project GrantsRoleSignal InductionSignal PathwaySignal TransductionT cell differentiationT cell responseT memory cellT-Cell DevelopmentT-LymphocyteT-Lymphocyte SubsetsTCF Transcription FactorTestingTherapeuticTranscription CoactivatorTranscription RepressorTranscriptional RegulationTumor AntigensUnited StatesUp-RegulationVaccinationViralViral CancerVirus Diseasesacute infectioncell typechronic infectioncytokinecytotoxicexhaustexhaustionextracellulargene repressiongenetic corepressorimmune checkpoint blockadeinsightinterleukin-15 receptormouse modelmutantpathogenprogenitorrecruitresponseself-renewalstemthymocytetranscription factortumor
项目摘要
PROJECT SUMMARY
CD8 T cells are critical for immune surveillance of both intracellular pathogens and cancer. Chronic and acute
antigen exposure entails distinct differentiation trajectories of CD8 T cells. In acute infection, naïve CD8 T cells
that recognize antigen undergo clonal expansion and differentiate into either cytotoxic effectors or quiescent
central memory cells (Tcm) that mediate rapid responses to subsequent infections. In settings of chronic
antigen exposure, such as cancer, CD8 T cells instead differentiate into to terminally exhausted (TEX) cells. TEX
have attenuated proliferative, cytokine-secretory, and cytolytic functions relative to the effector cells elicited by
acute infection. Although they still exert a significant level of viral control, TEX are unable to sustain durable
responses and require constant replenishment from a pool of quiescent, stem-like T progenitor exhausted
(TPEX). Importantly, immune checkpoint blockade therapy acts on TPEX to mobilize T cell responses to tumor
antigens. Despite the therapeutic imperative to elicit Tcm in response to vaccination and TPEX in responses to
cancer, the molecular mechanisms by which these T cell subsets develop are incompletely understood. It is
known that the transcription factor (TF) TCF-1 is required for both Tcm and TPEX populations and is
downregulated during the differentiation of effector and exhausted CD8 T cells. Although pro-inflammatory
cytokines such as IL-2 and IL-12 are known to induce the downregulation of TCF-1 (encoded by Tcf7), it is
unclear how these extracellular cues are integrated to regulate TCF-1 expression during the fate decisions of
effector and TEX differentiation. It is also incompletely understood how TCF-1 contributes to the establishment
of unique transcriptional profiles of TPEX and Tcm despite the dependency of both cell subsets on this TF. The
proposed study seeks to address these gaps in knowledge by testing the central hypotheses (1) that self-
amplification of IL-2 receptor signaling through upregulation of the IL-2R alpha chain (Il2ra) promotes
downregulation of TCF-1 by direct repression of Tcf7 by the IL-2-inducible TFs AP4 and Blimp1 and (2) that
differential engagement of TLE family co-repressors and intrinsic HDAC activity by TCF-1 in TPEX and Tcm result
in subset-specific transcriptional regulation by TCF-1. The research project will interrogate the necessity of IL-
2R self-amplification in terminal differentiation by ablating IL-2R signaling-responsive cis-regulatory elements in
the Il2ra and Tcf7 loci in mouse models of chronic and acute infections. The requirements of TLE co-repressor
recruitment and HDAC activity in TPEX and Tcm will be interrogated by complementing Tcf7-deficient CD8 T cells
with Tcf7 mutants deficient in either HDAC or TLE co-repressor binding activity and infecting mice with chronic
or acute LCMV. The proposed research project is expected to advance the long-term objective of determining
the molecular basis by which Tcm and TPEX fate decisions are made, with the ultimate goal of engineering
durable CD8 T cell responses to infection and cancer.
项目摘要
CD 8 T细胞对于细胞内病原体和癌症的免疫监视至关重要。慢性和急性
抗原暴露需要CD 8 T细胞的不同分化轨迹。在急性感染中,初始CD 8 T细胞
其识别抗原经历克隆扩增并分化成细胞毒性效应物或静止
中央记忆细胞(Tcm)介导对随后感染的快速反应。在慢性疾病的环境中,
抗原暴露,如癌症,CD 8 T细胞反而分化为终末耗竭(TEX)细胞。Tex
相对于由以下引起的效应细胞,具有减弱的增殖、分泌肾上腺素和细胞溶解功能:
急性感染虽然他们仍然发挥显着水平的病毒控制,特克斯是无法维持持久的
反应,并需要从一池疲惫不堪的静止、干细胞样T祖细胞中不断补充
(TPEX)。重要的是,免疫检查点阻断疗法作用于TPEX以动员T细胞对肿瘤的应答。
抗原尽管治疗必须引起Tcm对疫苗接种的反应和TPEX对疫苗接种的反应,
癌症,这些T细胞亚群发育的分子机制尚未完全了解。是
已知转录因子(TF)TCF-1是Tcm和TPEX群体所需的,
在效应和耗尽的CD 8 T细胞的分化过程中下调。虽然促炎性
已知细胞因子如IL-2和IL-12诱导TCF-1(由Tcf 7编码)的下调,
目前还不清楚这些细胞外信号是如何整合到TCF-1的表达中的,
效应子和TEX分化。也不完全了解TCF-1如何有助于建立
TPEX和Tcm的独特的转录谱,尽管这两个细胞亚群依赖于这种TF。的
拟议的研究试图通过测试中心假设(1)自我-
通过上调IL-2 R α链(Il 2 ra)扩增IL-2受体信号传导促进
通过IL-2诱导的TF AP 4和Blimp 1直接抑制Tcf 7下调TCF-1,以及(2)
TPEX和Tcm结果中TCF-1对TLE家族辅阻遏物和固有HDAC活性的差异性接合
在TCF-1的亚组特异性转录调节中。该研究项目将询问IL-
通过切除IL-2 R信号转导应答顺式调节元件在终末分化中的2 R自身扩增
慢性和急性感染小鼠模型中的Il 2 ra和Tcf 7基因座。TLE辅阻遏物的要求
TPEX和Tcm中的募集和HDAC活性将通过补充Tcf 7缺陷的CD 8 T细胞来检测
用HDAC或TLE共阻遏物结合活性缺陷的Tcf 7突变体感染小鼠,
或急性LCMV。拟议的研究项目预计将推进确定
Tcm和TPEX命运决定的分子基础,最终目标是工程
CD 8 T细胞对感染和癌症的持久反应。
项目成果
期刊论文数量(0)
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