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System Dynamics of PD-1 Signaling in T Cells

System Dynamics of PD-1 Signaling in T Cells
T 细胞中 PD-1 信号传导的系统动力学
批准号:
10211871
负责人:
William S Hlavacek
金额:
$78.46万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-05-03 至 2027-04-30
关键词:
AccountingAffinityAntibodiesAntigen PresentationAntigen-Presenting CellsAntigensAutoimmune DiseasesAutoimmunityB7-DC antigenBioinformaticsBiological AssayCD28 geneCD8-Positive T-LymphocytesCD80 geneCD86 geneCell LineCellsChronicClustered Regularly Interspaced Short Palindromic RepeatsComplementDataDiseaseEngineeringEvaluationFamilyFluorescence MicroscopyFormulationHumanITAMImmuneImmune TargetingImmune responseImmune systemImmunologic SurveillanceImmunotherapyIndividualInnate Immune ResponseInterventionInvestigationKnowledgeLabelLigandsMachine LearningMass Spectrum AnalysisMeasurementMeasuresMediatingMembraneMethodsModelingMolecularMonitorNR0B2 geneOncologyPTPN11 genePTPN6 genePatternPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhosphotyrosinePlayPopulationProtein DephosphorylationProtein Tyrosine KinaseProtein Tyrosine PhosphataseProteinsProtocols documentationReagentReceptor SignalingRoleSYK geneSamplingSignal TransductionSignaling ProteinSiteStructural ModelsSystemSystems BiologyT-Cell ActivationT-Cell ReceptorT-LymphocyteTechniquesTestingTherapeutic antibodiesTimeToll-like receptorsTyrosine PhosphorylationValidationWestern BlottingZAP-70 Geneadaptive immune responsearmbasecancer cellchronic infectiondectin 1exhaustionexperimental studyimmune activationimmune checkpointimprovedinterestmathematical modelneoplastic cellnovel therapeutic interventionparticlepathogenpathogenic fungusphosphoproteomicspredictive modelingpreventprogrammed cell death ligand 1programmed cell death protein 1receptorrecruitresponsesingle molecule

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中文摘要
翻译
项目摘要/摘要 获得性免疫反应受T细胞受体(TCR)信号支配,TCR信号决定命运和 T细胞的活动(辅助者、效应者等)。TCR及其信号伙伴整合了抗原识别 信号和第二信号,它们携带关于抗原呈递的上下文的信息 发生的。第二种信号既可以是刺激性的,也可以是抑制性的:刺激性信号对T细胞是必不可少的 激活,而抑制信号(也称为检查点)负责T细胞耗尽和 抗原耐受性。刺激的第二信号是由免疫系统的先天手臂产生的,当 例如,通过Toll样受体的信号诱导B7家族配体B7-1(CD80)和B7-2的表达 (CD86)表达于抗原提呈细胞。B7-1/B7-2的表达表明正在发生抗原提呈 在持续的先天免疫反应的背景下。B7-1和B7-2被TCR CD28识别 能有效增强TCR产生的T细胞激活信号的辅助受体。抑制性第二信号出现 在慢性刺激TCR信号的过程中。它们对于限制附带损害很重要。 由免疫反应和避免自身免疫引起,但它们也可能是有害的。为 例如,肿瘤细胞通常表达B7-家族配体B7-H1(PD-L1/CD274)和B7-DC(PD-DCs)。 L2/CD273),可被PD-1识别,PD-1是一种TCR辅助受体,可抑制TCR产生的T细胞激活 信号。B7-H1/B7-DC的表达向肿瘤细胞传递免疫豁免。出于这些和其他原因,它是 当务之急是提高我们对检查站信号的基本理解。在这里,我们建议将 PD-1调节Jurkat E6-1、HUT 78和TALL-104细胞酪氨酸磷酸化的动力学 CRISPR工程细胞来源于这些亲本细胞系和原代人类CD8细胞。我们会申请 定量质谱学(MS)以获得无偏的、几乎全面的磷酸酪氨酸图像 T细胞群体中有无PD-1/CD28共受体信号的(PTyr)位点丰度随时间的变化 并且跨越各种条件。同时,使用荧光显微镜和工程SH2结构域亲和 试剂,我们将表征TCR,CD28和PD-1的多位点磷酸化的单分子模式。 我们还将测量这些细胞胞质信号伙伴的膜募集寿命 感受器。所产生的数据将用于驱动详细的 TCR信号机制模型解释了CD28和PD-1共激活的影响。虽然PD-1 被视为一个招募磷酸酶的平台,它抵消了来自激酶的激活信号,我们将 评估关于PD-1如何潜在地产生T细胞激活的积极信号的具体假设。 这些假说的动机是这样一个事实,即PD-1最典型的信号伙伴是蛋白质 酪氨酸磷酸酶,SHP1和SHP2,已知在其他环境中通过促进细胞激活, 例如,介导抑制pTyr位点的去磷酸化。模型预测将得到检验。
英文摘要
PROJECT SUMMARY/ABSTRACT Adaptive immune responses are governed by T cell receptor (TCR) signaling, which determines the fates and activities of T cells (helper, effector, etc.). The TCR and its signaling partners integrate antigen-recognition signals and second signals, which carry information about the context in which antigen presentation is occurring. Second signals can be either stimulatory or inhibitory: stimulatory signals are essential for T cell activation, whereas inhibitory signals (also called checkpoints) are responsible for T cell exhaustion and antigen tolerance. Stimulatory second signals are generated by the innate arm of the immune system when, for example, signaling by Toll-like receptors induces expression of the B7-family ligands B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells. Expression of B7-1/B7-2 indicates that antigen presentation is occurring within the context of an ongoing innate immune response. B7-1 and B7-2 are recognized by CD28, a TCR coreceptor that potently enhances TCR-generated T-cell activation signals. Inhibitory second signals arise during the course of chronic stimulation of TCR signaling. They are important for limiting the collateral damage caused by an immune response and avoidance of autoimmunity, but they can also be deleterious. For example, tumor cells commonly express the B7-family ligands B7-H1 (PD-L1/CD274) and B7-DC (PD- L2/CD273), which are recognized by PD-1, a TCR coreceptor that inhibits TCR-generated T-cell activation signals. B7-H1/B7-DC expression conveys immune privilege to tumor cells. For these and other reasons, it is imperative that we improve our basic understanding of checkpoint signaling. Here, we propose to characterize the dynamics of PD-1-regulated tyrosine phosphorylation in Jurkat E6-1, HuT 78, and TALL-104 cells, CRISPR-engineered cells derived from these parental cell lines, and primary human CD8+ cells. We will apply quantitative mass spectrometry (MS) to obtain an unbiased, nearly comprehensive picture of phosphotyrosine (pTyr) site abundances with and without PD-1/CD28 coreceptor signaling in populations of T cells over time and across conditions. Concurrently, using fluorescence microscopy and engineered SH2 domain affinity reagents, we will characterize single-molecule patterns of multisite phosphorylation for TCR, CD28, and PD-1. We will also measure membrane-recruitment lifetimes for individual cytosolic signaling partners of these receptors. The resulting data will be used to drive the formulation and parameterization of a detailed mechanistic model for TCR signaling accounting for the effects of CD28 and PD-1 coactivation. Although PD-1 is viewed as a platform for recruitment of phosphatases that counteract activation signals from kinases, we will evaluate specific hypotheses about how PD-1 could potentially generate positive signals for T-cell activation. These hypotheses are motivated by the fact that the best characterized signaling partners of PD-1 are protein tyrosine phosphatases, SHP1 and SHP2, which are known to promote cell activation in other contexts by, for example, mediating the dephosphorylation of inhibitory pTyr sites. Model predictions will be tested.
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System Dynamics of PD-1 Signaling in T Cells
  • 批准号:
    10399590
  • 项目类别:
  • 资助金额:
    $78.53万
  • 财政年份:
    2021
  • 负责人:
    William S Hlavacek
  • 依托单位:
Multiscale Modeling to Optimize Inhibition of Oncogenic ERK Pathway Signaling
  • 批准号:
    10558581
  • 项目类别:
  • 资助金额:
    $66.96万
  • 财政年份:
    2020
  • 负责人:
    William S Hlavacek
  • 依托单位:
Multiscale Modeling to Optimize Inhibition of Oncogenic ERK Pathway Signaling
  • 批准号:
    10337242
  • 项目类别:
  • 资助金额:
    $67.44万
  • 财政年份:
    2020
  • 负责人:
    William S Hlavacek
  • 依托单位:
Computational Model of Autophagy-Mediated Survival in Chemoresistant Lung Cancer
  • 批准号:
    9547104
  • 项目类别:
  • 资助金额:
    $48.42万
  • 财政年份:
    2017
  • 负责人:
    William S Hlavacek
  • 依托单位:
海外基金