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:10077818
- 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 2022-12-31
- 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.
项目概要
由于其频率升高、自我更新能力强以及效应功能快速获得
重新激活后,记忆 T 细胞抵御二次挑战的能力增强。这
记忆 T 细胞的产生是众多疫苗和免疫治疗策略的焦点。最多
(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细胞可以
在初级效应反应期间鉴定,表明激活的 T 细胞接收分化信号
在对影响记忆命运分化的感染的初级反应期间。我们最近展示了
T 细胞受体 (TCR) 信号在驱动 CD4+ 记忆 T 细胞分化中发挥关键作用。 TCR 是
能够与 MHC II 类结合抗原 (pMHCII) 进行持续相互作用的偏向于
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
朝向终末效应细胞分化。我们将通过使用不同的感染模型来建立这些研究
定义 TCR 依赖性激活和转录程序的各个方面,从而导致形成
淋巴驻留、循环和组织驻留 CD4+ 记忆 T 细胞。我们提出三个关键问题。第一的,
TCR信号强度在记忆T细胞的形成中起什么作用?我们将探讨以下假设:
体内 TCR 信号强度增加可驱动终末效应 T 细胞分化,而 TCR 信号较弱
强度允许记忆T细胞形成。其次,与TCR相关的结合参数有哪些?
记忆T细胞发育?我们将通过施加力来测量二维亲和力和键寿命
TCR 是效应器偏向或记忆偏向的。我们将测试债券寿命将预测的假设
TCR 依赖性记忆分化。三、控制记忆的转录程序有哪些
形成?我们将测试记忆T细胞中差异表达分子的机制作用
主要效应反应期间的前体,包括 TCF-1。我们预计该决议
本研究中提出的问题将提供一个框架,用于更详细地确定如何
记忆 T 细胞形成并识别直接调节 CD4+ 效应器和记忆 T 的治疗方法
体内细胞分化。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Matthew A Williams其他文献
Matthew A Williams的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10318962 - 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:
8604667 - 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 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:
相似国自然基金
抗原非特异性B细胞进入生发中心并实现亲和力成熟的潜力与调控机制
- 批准号:32370941
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
靶向KRAS新抗原TCR-T细胞的亲和力优化和抗肿瘤功能分析
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于新抗原受体可变域的赭曲霉毒素A竞争物与VHH抗体互作的亲和力调控机制
- 批准号:32102067
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
免疫分析异源竞争模式中半抗原设计机制研究
- 批准号:31800776
- 批准年份:2018
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
建立一种基于抗原抗体共展示技术的膜蛋白抗体文库筛查系统
- 批准号:81773618
- 批准年份:2017
- 资助金额:48.0 万元
- 项目类别:面上项目
相似海外基金
Immunomodulatory ligand B7-1 targets p75 neurotrophin receptor in neurodegeneration
免疫调节配体 B7-1 在神经变性中靶向 p75 神经营养蛋白受体
- 批准号:
10660332 - 财政年份:2023
- 资助金额:
$ 48.27万 - 项目类别:
Broadly neutralizing SARS-CoV-2 peptidic knobs
广泛中和 SARS-CoV-2 肽旋钮
- 批准号:
10735902 - 财政年份:2023
- 资助金额:
$ 48.27万 - 项目类别:
TOX-driven CD8 T cell differentiation and dysfunction in tumors
TOX驱动的肿瘤中CD8 T细胞分化和功能障碍
- 批准号:
10586679 - 财政年份:2023
- 资助金额:
$ 48.27万 - 项目类别:
Development of antigen multimers for CAR T cell detection and functional profiling
开发用于 CAR T 细胞检测和功能分析的抗原多聚体
- 批准号:
10741209 - 财政年份:2023
- 资助金额:
$ 48.27万 - 项目类别:
B Cell Biology in the Context of Infectious Diseases, Autoimmunity and B Cell Cancers
传染病、自身免疫和 B 细胞癌症背景下的 B 细胞生物学
- 批准号:
10683443 - 财政年份:2023
- 资助金额:
$ 48.27万 - 项目类别: