TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection
感染后 CD4 T 细胞的 TCR 依赖性激活、功能分化和记忆形成
基本信息
- 批准号:10318962
- 负责人:
- 金额:$ 48.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-17 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffinityAntigensAutomobile DrivingBacterial InfectionsBiologyCD4 Positive T LymphocytesCD8B1 geneCell CountCell Differentiation processCell physiologyCellsCellular biologyCharacteristicsClonal ExpansionCommunicable DiseasesCuesDevelopmentEffector CellFrequenciesGene Expression ProfileGenerationsGenetic TranscriptionHeterogeneityIL2RA geneImmuneImmune systemImmunityImmunologic MemoryImmunotherapeutic agentInfectionLymphoidMHC Class II GenesMalignant NeoplasmsMeasurementMeasuresMediatingMemoryModelingOutcomePlayPopulationReceptor SignalingResolutionRoleSignal TransductionSystemT cell differentiationT memory cellT-Cell ActivationT-Cell DevelopmentT-Cell ReceptorT-LymphocyteT-cell receptor repertoireTestingTherapeuticTissuesVaccinationVaccinesVirus Diseasesantigen bindingbasecytokinedesigndifferential expressioneffector T cellin vivoinsightmemory CD4 T lymphocytenovelpathogenprogramsreceptor bindingresponseself-renewaltherapeutic targettooltranscription factortranscriptome
项目摘要
Project Summary
Because of their elevated frequency, ability to self-renew and rapid acquisition of effector function
following re-activation, memory T cells have an enhanced ability to protect from secondary challenge. The
generation of memory T cells is the focal point of numerous vaccine and immunotherapeutic strategies. Most
(90-95%) effector T cells die after pathogen clearance, but those fated to become memory cells can be
identified during the primary effector response, showing that activated T cells receive differentiation cues
during the primary response to infection that influence memory fate differentiation. We have recently shown
that T cell receptor (TCR) signals play a key role in driving CD4+ memory T cell differentiation. TCRs that are
able to engage MHC Class II-bound antigen (pMHCII) in sustained interactions are biased towards the
formation of long-lived memory, while TCRs that engage in short-lived interactions with antigen are biased
towards terminal effector cell differentiation. We will build on those studies by using diverse infectious models
to define aspects of the TCR-dependent activation and transcriptional program that leads to the formation of
lymphoid-resident, circulating and tissue-resident CD4+ memory T cells. We pose three key questions. First,
what is the role of TCR signal strength in the formation of memory T cells? We will explore the hypothesis that
increasing TCR signal strength in vivo drives terminal effector T cell differentiation, while weaker TCR signal
strength allows memory T cell formation. Second, what are the TCR binding parameters associated with
memory T cell development? We will measure 2D affinity and bond lifetime with the application of force for
TCRs at that are effector-biased or memory-biased. We will test the hypothesis that bond lifetimes will predict
TCR-dependent memory differentiation. Third, what are the transcriptional programs that control memory
formation? We will test the mechanistic role of molecules that are differentially expressed in memory T cell
precursors during the primary effector response, including TCF-1. We anticipate that resolution of the
questions posed in this study will provide a framework for determining in greater mechanistic detail how
memory T cells form and identify therapeutic approaches for directly modulating CD4+ effector and memory T
cell differentiation in vivo.
项目摘要
由于它们的频率升高,自我更新能力和快速获得效应器功能
在再激活后,记忆T细胞具有增强的保护免受二次攻击的能力。的
记忆T细胞的产生是许多疫苗和免疫策略的焦点。最
(90-95%)效应T细胞在病原体清除后死亡,但那些注定成为记忆细胞的T细胞可能会死亡。
在初级效应反应期间鉴定,表明活化的T细胞接受分化提示,
在对感染的主要反应中影响记忆命运分化。我们最近的研究表明
T细胞受体(TCR)信号在驱动CD 4+记忆T细胞分化中起关键作用。TCR是
能够在持续的相互作用中与MHC II类结合抗原(pMHCII)结合的抗原偏向于
长期记忆的形成,而与抗原进行短期相互作用的TCR是有偏见的。
向终端效应细胞分化。我们将在这些研究的基础上,
为了定义导致以下形成的TCR依赖性激活和转录程序的方面,
淋巴驻留、循环和组织驻留CD 4+记忆T细胞。我们提出三个关键问题。第一、
TCR信号强度在记忆T细胞形成中的作用是什么?我们将探讨一个假设,
体内增加TCR信号强度驱动末端效应T细胞分化,而较弱的TCR信号强度驱动末端效应T细胞分化。
强度允许记忆T细胞形成。第二,TCR结合参数是什么,
记忆T细胞发育我们将测量2D亲和力和键寿命与力的应用,
TCR是效应器偏置或记忆偏置的。我们将检验一个假设,即键的寿命将预测
TCR依赖的记忆分化。第三,控制记忆的转录程序是什么
阵型?我们将测试在记忆T细胞中差异表达的分子的机制作用,
在初级效应器反应期间的前体,包括TCF-1。我们预计,
本研究中提出的问题将提供一个框架,用于更详细地确定
记忆T细胞形成并鉴定直接调节CD 4+效应子和记忆T细胞的治疗方法
体内细胞分化。
项目成果
期刊论文数量(3)
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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Matthew A Williams其他文献
MP81-17 DEVELOPING IMPROVED E-LEARNING ANATOMY RESOURCES FOR UNDERGRADUATE MEDICAL STUDENTS: MALE REPRODUCTIVE ANATOMY, A CASE STUDY
- DOI:
10.1016/j.juro.2017.02.2543 - 发表时间:
2017-04-01 - 期刊:
- 影响因子:
- 作者:
Matthew A Williams;Jessica Caterson;Christopher Horton;Tom Cosker - 通讯作者:
Tom Cosker
Matthew A Williams的其他文献
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{{ truncateString('Matthew A Williams', 18)}}的其他基金
TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection
感染后 CD4 T 细胞的 TCR 依赖性激活、功能分化和记忆形成
- 批准号:
10077818 - 财政年份:2018
- 资助金额:
$ 48.27万 - 项目类别:
Recruitment of melanoma-specific CD4+ T cells
黑色素瘤特异性 CD4 T 细胞的募集
- 批准号:
9304062 - 财政年份:2016
- 资助金额:
$ 48.27万 - 项目类别:
Recruitment of melanoma-specific CD4+ T cells
黑色素瘤特异性 CD4 T 细胞的募集
- 批准号:
9179396 - 财政年份:2016
- 资助金额:
$ 48.27万 - 项目类别:
The role of antigenic stimulatory strength in the selection and differentiation o
抗原刺激强度在选择和分化中的作用
- 批准号:
8420504 - 财政年份:2010
- 资助金额:
$ 48.27万 - 项目类别:
The role of antigenic stimulatory strength in the selection and differentiation o
抗原刺激强度在选择和分化中的作用
- 批准号:
7889307 - 财政年份:2010
- 资助金额:
$ 48.27万 - 项目类别:
The role of antigenic stimulatory strength in the selection and differentiation o
抗原刺激强度在选择和分化中的作用
- 批准号:
8018660 - 财政年份:2010
- 资助金额:
$ 48.27万 - 项目类别:
The role of antigenic stimulatory strength in the selection and differentiation o
抗原刺激强度在选择和分化中的作用
- 批准号:
8212268 - 财政年份:2010
- 资助金额:
$ 48.27万 - 项目类别:
The role of antigenic stimulatory strength in the selection and differentiation o
抗原刺激强度在选择和分化中的作用
- 批准号:
8604667 - 财政年份:2010
- 资助金额:
$ 48.27万 - 项目类别:
The role of IL-2 in promoting CD8 memory T cell responsiveness
IL-2 在促进 CD8 记忆 T 细胞反应性中的作用
- 批准号:
7390688 - 财政年份:2007
- 资助金额:
$ 48.27万 - 项目类别:
The role of IL-2 in promoting CD8 memory T cell responsiveness
IL-2 在促进 CD8 记忆 T 细胞反应性中的作用
- 批准号:
7136618 - 财政年份:2007
- 资助金额:
$ 48.27万 - 项目类别:
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