Defining modes of helper T cell motility within inflamed tissues
定义发炎组织内辅助 T 细胞的运动模式
基本信息
- 批准号:8261449
- 负责人:
- 金额:$ 2.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-02-14 至 2012-07-20
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesAntigen-Presenting CellsArchitectureBehaviorCD4 Positive T LymphocytesCell Adhesion MoleculesCell physiologyCellsChronicDataDendritic CellsDermisDiseaseEffector CellEnvironmentEventExtracellular MatrixFeedbackFoundationsGeneticGoalsHelper-Inducer T-LymphocyteImageImmuneImmune responseImmunologyIn VitroInfectionInflammationIntegrinsInterleukin-13Interleukin-4Interleukin-5LaboratoriesLeishmaniaLeishmania majorLeukocytesLifeLocationLymphocyteLymphoid TissueMediatingMesenchymalMicroscopyModelingMolecularMovementMusMyosin Type IINatureParasitesParasitic infectionPathologyPathway interactionsPatternPeripheralPhenotypePhotonsPopulationResearch TrainingResidenciesSelectinsSignal TransductionSiteSmall Interfering RNASolidStreamSurfaceSystemT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTestingTh1 CellsTh2 CellsTherapeuticTissuesTumor Necrosis Factor-BetaWorkantibody inhibitorbasecell motilitychemokinecytokinedesignin vivointerstitialintravital microscopylymph nodesnovelpathogenpublic health relevancereceptorresponsesmall moleculetherapeutic targettumor
项目摘要
DESCRIPTION (provided by applicant): Leukocytes have been shown to utilize different modes of motility in vitro, depending on the nature of their surrounding environment. Using a system of intravital 2-photon microscopy to image live T cells within the inflamed dermis of a mouse, we have observed two distinct interstitial crawling phenotypes that were displayed by functionally discrete CD4+ T cell populations. Th1 cells moved rapidly with amoeboid-like motility while Th2 cells crawled with mesenchymal-like motility. These two modes suggest the mechanisms underlying movement of these functionally distinct T cells are distinct. Given the feedback between the extracellular matrix and intracellular signaling through surface receptors (such as integrins), these observations have relevance in a model of Leishmania major, in which our previous data has suggests that there are functional alterations to T cells in the locally infected tissue that may restrict Th1 accumulation. Thus, we will test the hypotheses that 1) Th1 and Th2 effectors T cells utilize different molecular machinery for motility during in vivo interstitial crawling and 2) motility is modified during parasitic L. major infection. Specific Aim 1: Do effector Th1 and Th2 cells utilize distinct mechanisms to crawl in sites of inflammation? Currently, two main modes of interstitial crawling have been described by cell biologists; integrin-dependent (mesenchymal) and integrin-independent, myosin II-dependent (amoeboid) motility. The objective of this aim is to determine the molecular means by which distinct helper T cell populations crawl within the interstitial space of the inflamed dermis. Candidate molecular pathways will be disrupted by antibody-blockade, genetic deletion and siRNA and the effects on motility determined by intravital 2-photon microscopy. Specific Aim 2: Can the migratory and crawling patterns of helper T cells be modulated by local changes induced by a pathogen? In addition to the immunological responses that accompany chronic infection, pathogens such as L. major can induce significant changes in the local milieu. L. major could modulate T cell motility in trans through pathogen-driven changes in architecture and composition of the ECM of the local tissue and in cis through modulating the chemokines and adhesion molecules expressed by the infected host cells. These changes can result local microenvironments that are dramatically different from steady state and even non-parasitized inflamed tissue. The goal of this aim is to evaluate the effects of the L. major-infected tissue microenvironment on Th1 and Th2 cell crawling, as well as the ability of parasitized antigen presenting cells to interact with the different effector T cells subsets.
PUBLIC HEALTH RELEVANCE: Using a system of intravital microscopy to image live T cells within the inflamed dermis of a mouse, we have observed two unique crawling phenotypes that were displayed by functionally distinct CD4+ T cell populations. In the current research training plan, we will test whether the different crawling phenotypes observed utilize unique molecular mechanisms in vivo. An understanding of mechanisms employed by functionally distinct effector T cells could present means of preferentially manipulating subsets of tissue-resident effector cells, potentially offering great therapeutic potential for many disease states.
描述(由申请人提供):白细胞已被证明可以利用不同的体外运动模式,具体取决于其周围环境的性质。使用活体 2 光子显微镜系统对小鼠发炎真皮内的活 T 细胞进行成像,我们观察到两种不同的间质爬行表型,这些表型由功能上离散的 CD4+ T 细胞群显示。 Th1 细胞以类似变形虫的运动方式快速移动,而 Th2 细胞则以类似间充质的运动方式爬行。这两种模式表明这些功能不同的 T 细胞运动的机制是不同的。鉴于细胞外基质和细胞内信号之间通过表面受体(例如整合素)进行反馈,这些观察结果与重大利什曼原虫模型相关,我们之前的数据表明,局部感染组织中的 T 细胞存在功能改变,可能会限制 Th1 积累。因此,我们将测试以下假设:1) Th1 和 Th2 效应 T 细胞在体内间质爬行过程中利用不同的分子机制进行运动,2) 在寄生 L.major 感染期间运动发生改变。具体目标 1:效应 Th1 和 Th2 细胞是否利用不同的机制在炎症部位爬行?目前,细胞生物学家描述了两种主要的间质爬行模式:整合素依赖性(间充质)和整合素独立、肌球蛋白 II 依赖性(变形虫)运动。该目的的目的是确定不同的辅助 T 细胞群在发炎真皮间隙内爬行的分子手段。候选分子途径将被抗体阻断、基因缺失和 siRNA 破坏,并通过活体 2 光子显微镜确定对运动的影响。具体目标 2:辅助 T 细胞的迁移和爬行模式是否可以通过病原体引起的局部变化来调节?除了伴随慢性感染的免疫反应外,大型利斯特氏菌等病原体还可引起局部环境的显着变化。 L. Major 可以通过病原体驱动的局部组织 ECM 结构和组成的变化来调节 T 细胞的反式运动,也可以通过调节受感染宿主细胞表达的趋化因子和粘附分子来调节 T 细胞的顺式运动。这些变化可能导致局部微环境与稳态甚至非寄生的发炎组织显着不同。该目的的目的是评估 L. Major 感染的组织微环境对 Th1 和 Th2 细胞爬行的影响,以及寄生的抗原呈递细胞与不同效应 T 细胞亚群相互作用的能力。
公共健康相关性:使用活体显微镜系统对小鼠发炎真皮内的活 T 细胞进行成像,我们观察到功能不同的 CD4+ T 细胞群表现出两种独特的爬行表型。在当前的研究培训计划中,我们将测试观察到的不同爬行表型是否利用体内独特的分子机制。了解功能不同的效应 T 细胞所采用的机制可以提供优先操纵组织驻留效应细胞子集的方法,从而可能为许多疾病状态提供巨大的治疗潜力。
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 }}
Michael Glen Overstreet其他文献
Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay
- DOI:
10.1016/j.xcrm.2024.101804 - 发表时间:
2024-11-19 - 期刊:
- 影响因子:
- 作者:
Tristan Tay;Gayathri Bommakanti;Elizabeth Jaensch;Aparna Gorthi;Iswarya Karapa Reddy;Yan Hu;Ruochi Zhang;Aatman S. Doshi;Sin Lih Tan;Verena Brucklacher-Waldert;Laura Prickett;James Kurasawa;Michael Glen Overstreet;Steven Criscione;Jason Daniel Buenrostro;Deanna A. Mele - 通讯作者:
Deanna A. Mele
Michael Glen Overstreet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('Michael Glen Overstreet', 18)}}的其他基金
Defining modes of helper T cell motility within inflamed tissues
定义发炎组织内辅助 T 细胞的运动模式
- 批准号:
8060788 - 财政年份:2011
- 资助金额:
$ 2.72万 - 项目类别:
相似海外基金
Tri-Signal Artificial Antigen Presenting Cells for Cancer Immunotherapy
用于癌症免疫治疗的三信号人工抗原呈递细胞
- 批准号:
10751133 - 财政年份:2023
- 资助金额:
$ 2.72万 - 项目类别:
Microfluidic Precision Engineered Artificial Antigen Presenting Cells for Cancer Immunotherapy
用于癌症免疫治疗的微流控精密工程人工抗原呈递细胞
- 批准号:
10696138 - 财政年份:2022
- 资助金额:
$ 2.72万 - 项目类别:
The role of microglia as antigen presenting cells in Globoid Cell Leukodystrophy
小胶质细胞作为抗原呈递细胞在球状细胞脑白质营养不良中的作用
- 批准号:
10663066 - 财政年份:2022
- 资助金额:
$ 2.72万 - 项目类别:
The role of microglia as antigen presenting cells in Globoid Cell Leukodystrophy
小胶质细胞作为抗原呈递细胞在球状细胞脑白质营养不良中的作用
- 批准号:
10537159 - 财政年份:2022
- 资助金额:
$ 2.72万 - 项目类别:
Analysis of the function of antigen-presenting cells present in the stroma of colorectal cancer and the intracellular microbiome
结直肠癌基质中抗原呈递细胞和细胞内微生物组的功能分析
- 批准号:
21K08723 - 财政年份:2021
- 资助金额:
$ 2.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Class II artificial antigen presenting cells for cancer immunotherapy
用于癌症免疫治疗的 II 类人工抗原呈递细胞
- 批准号:
10156950 - 财政年份:2021
- 资助金额:
$ 2.72万 - 项目类别:
The role of CX3CR1+ antigen presenting cells in T cell selection and central tolerance"
CX3CR1抗原呈递细胞在T细胞选择和中枢耐受中的作用"
- 批准号:
10631854 - 财政年份:2021
- 资助金额:
$ 2.72万 - 项目类别:
Reprogramming Cancer Cells into Antigen Presenting Cells: Cancer Vaccination with mRNA Enabled by Charge-Altering Releasable Transporters
将癌细胞重编程为抗原呈递细胞:通过改变电荷的可释放转运蛋白实现 mRNA 的癌症疫苗接种
- 批准号:
10153927 - 财政年份:2021
- 资助金额:
$ 2.72万 - 项目类别:
Class II artificial antigen presenting cells for cancer immunotherapy
用于癌症免疫治疗的 II 类人工抗原呈递细胞
- 批准号:
10331830 - 财政年份:2021
- 资助金额:
$ 2.72万 - 项目类别:
Analysis on detrimental interplay between pathogenic helper T cells, inflammatory antigen-presenting cells and disease-associated microglia in chronic pathogenesis of multiple sclerosis
多发性硬化症慢性发病机制中致病性辅助 T 细胞、炎症抗原呈递细胞和疾病相关小胶质细胞之间的有害相互作用分析
- 批准号:
20K16294 - 财政年份:2020
- 资助金额:
$ 2.72万 - 项目类别:
Grant-in-Aid for Early-Career Scientists