Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering

通过细胞因子/趋化因子依赖性细胞聚类对炎症部位 T 细胞激活进行空间优化

基本信息

  • 批准号:
    10477325
  • 负责人:
  • 金额:
    $ 40.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-06-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT – PROJECT 2 Spatiotemporal control of effector T cell activation at sites of inflammation/infection is an essential yet poorly understood process. Most intravital imaging studies have concluded that T cells scan inflamed tissues in a random non-directional fashion. Therefore, how CD4+ T cells ultimately position themselves for effective anti- pathogen immunity remains elusive. For Th1 effectors the optimal location of effector T cell activation is likely dependent on the active range of secreted effector molecules such as IFNγ, estimated to be ~80 microns in cutaneous Leishmania major infection. Despite knowing some of the key cellular and molecular players essential for T cell accumulation at sites of inflammation, how they are spatially and temporally positioned and released remains a critical knowledge gap that hinders new approaches to therapeutic manipulation to enhance immunity to infection and to diminish autoimmune tissue damage. Using CXCL9/10 fluorescent reporter mice to visualize the cellular source/location of chemokine production and IV-MPM to track Th1 migration, we found chemokine producing cells were spatially restricted to perivascular clusters (PVC) that were enriched in MHC-IIhigh antigen presenting cells and that shaped the localization and motility of Th1 cells in the inflamed/infected dermis. Our overall hypothesis is that initial peripheral activation occurs in chemokine-rich peri-vascular clusters that serve to nucleate and amplify T cell recruitment and activation for efficient pathogen clearance. This nucleation step may facilitate efficient pathogen clearance but may also exacerbate the magnitude of immune damage in autoimmune settings. This proposal uses IV-MPM and photoactivation tools for spatiotemporal dissection of the organization, composition and impact of these chemokine `hubs' on Th1 activation and their role in optimizing protective immunity at foci of infection. Aim 1. Organization of chemokine-rich perivascular clusters via innate cell:Th1 cross-talk. To test the hypothesis that initial chemokine-rich PVCs serve to activate early Th1 `pioneers' entering the tissue and that Th1 cytokines drive a local positive amplification loop to boost subsequent Th1 cell recruitment. Aim 2. Functional impact of T cell activation within the clusters. We hypothesize that the positioning of both chemokine producing cells and antigen presentation within the PVCs serves to nucleate signals for efficient Th1 activation. Using in situ photoactivation, PA-GFP, we will mark Th1s within and outside the PVC and determine if activation within the PVC confers distinct functional advantages. Aim 3. Relationship between peri-vascular clusters and the infection foci. Chemokine-rich PNCs containing Th1 cells can be found 100-400µm from the site of primary infection. We hypothesize that early PVC nucleation is followed by local diaspora of activated Th1 cells that accumulate at infection foci.
项目摘要/摘要--项目2 在炎症/感染部位时空控制效应T细胞的激活是必要的,但也不是很好 了解流程。大多数活体成像研究得出结论,T细胞扫描炎症组织 随机非定向时尚。因此,CD4+T细胞最终如何定位为有效的抗- 病原体免疫仍然难以捉摸。对于Th1效应器,效应器T细胞激活的最佳位置可能是 取决于分泌的效应分子的活性范围,如干扰素γ,估计为~80微米 皮肤利什曼原虫重大感染。尽管知道一些关键的细胞和分子参与者 对于T细胞在炎症部位的聚集是必不可少的,它们是如何在空间和时间上定位和 被释放的仍然是一个关键的知识缺口,阻碍了治疗操作的新方法 增强对感染的免疫力,减少自身免疫组织损伤。 用CXCL9/10荧光报告鼠显示趋化因子产生的细胞来源/位置 和IV-MPM跟踪Th1的迁移,我们发现产生趋化因子的细胞在空间上受限于 血管周围簇(PVC),富含MHC-II高抗原提呈细胞,形成 Th1细胞在炎症/感染真皮中的定位和运动我们的总体假设是,最初 外周激活发生在富含趋化因子的血管周围簇中,这些簇用于核和 增强T细胞的募集和激活,以有效清除病原体。该成核步骤可以 促进病原体有效清除,但也可能加剧免疫损伤的程度 自身免疫设置。该方案使用IV-MPM和光激活工具来进行时空解剖 这些趋化因子“中枢”的组织、组成和对Th1激活的影响及其在 优化疫源地保护性免疫。 目的1.通过先天细胞组织富含趋化因子的血管周围簇:Th1串扰。为了测试 假设最初的富含趋化因子的PVCs可以激活早期Th1‘先锋’进入组织和 Th1细胞因子驱动局部正向扩增环,以促进随后的Th1细胞募集。 目的2.簇内T细胞活化的功能影响。我们假设, 产生趋化因子的细胞和PVCs内的抗原递呈都起到核化信号的作用 高效的Th1激活。使用原位光活化PA-GFP,我们将在PVC内部和外部进行标记 并确定在PVC内激活是否具有明显的功能优势。 目的3.血管周围簇与感染源的关系。富含趋化因子的PNC 在距初次感染部位100-400微米处可发现含有Th1细胞。我们很早就假设 在聚氯乙烯成核之后,活化的Th1细胞在局部扩散,聚集在感染灶处。

项目成果

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Deborah J Fowell其他文献

Deborah J Fowell的其他文献

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{{ truncateString('Deborah J Fowell', 18)}}的其他基金

Remodeling of Lymph Node-Derived Cytokine Responses at the Infected Tissue Site
受感染组织部位淋巴结衍生细胞因子反应的重塑
  • 批准号:
    10271765
  • 财政年份:
    2020
  • 资助金额:
    $ 40.24万
  • 项目类别:
DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response
DCM/整合素 TFH 定位线索支持生发中心反应
  • 批准号:
    10316662
  • 财政年份:
    2018
  • 资助金额:
    $ 40.24万
  • 项目类别:
DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response
DCM/整合素 TFH 定位线索支持生发中心反应
  • 批准号:
    10509381
  • 财政年份:
    2018
  • 资助金额:
    $ 40.24万
  • 项目类别:
ECM/Integrin Tfh positioning cues for support of the germinal center response
ECM/整合素 Tfh 定位线索支持生发中心反应
  • 批准号:
    10053300
  • 财政年份:
    2018
  • 资助金额:
    $ 40.24万
  • 项目类别:
DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response
DCM/整合素 TFH 定位线索支持生发中心反应
  • 批准号:
    10287490
  • 财政年份:
    2018
  • 资助金额:
    $ 40.24万
  • 项目类别:
Tissue regulation of T cell function
T 细胞功能的组织调节
  • 批准号:
    9065651
  • 财政年份:
    2014
  • 资助金额:
    $ 40.24万
  • 项目类别:
Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering
通过细胞因子/趋化因子依赖性细胞聚类对炎症部位 T 细胞激活进行空间优化
  • 批准号:
    10241369
  • 财政年份:
    2014
  • 资助金额:
    $ 40.24万
  • 项目类别:
Tissue Regulation of T Cell Function
T 细胞功能的组织调节
  • 批准号:
    9791597
  • 财政年份:
    2014
  • 资助金额:
    $ 40.24万
  • 项目类别:
Tissue Regulation of T Cell Function
T 细胞功能的组织调节
  • 批准号:
    10689168
  • 财政年份:
    2014
  • 资助金额:
    $ 40.24万
  • 项目类别:
Tissue Regulation of T Cell Function
T 细胞功能的组织调节
  • 批准号:
    10477304
  • 财政年份:
    2014
  • 资助金额:
    $ 40.24万
  • 项目类别:

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