The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity

循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制

基本信息

  • 批准号:
    RGPIN-2015-05674
  • 负责人:
  • 金额:
    $ 2.55万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2018
  • 资助国家:
    加拿大
  • 起止时间:
    2018-01-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

BACKGROUND:***The orchestration of T-cell responses by innate immune cells such as macrophages is a hallmark of adaptive immunity. The effect of cytokine production and cell-cell contact of macrophage subsets has been well described for CD4+ T-cell subset differentiation, while their control of CD8+ T-cell activity and cytolytic (CTL) function remains unclear. Blood-derived macrophages have been recently described to polarize into M1, M2a, 2b and 2c subsets, establishing inflammatory, immunoregulatory or tissue-repairing cytokine milieus. In addition, the role of tissue-specific macrophages in maintaining immune tolerance and balancing the immune response and tissue destructive effects of infiltrating CD8+ T-cells remains to be fully described. For example, liver resident macrophages (Kupffer cells, KC, and hepatic stellate cells, HSC) have recently been described to polarize to M1- and M2-like phenotypes in non-alcoholic fatty liver disease, yet their potential for M2a, 2b or 2c subset differentiation has not been investigated. The inherent pro- and anti-inflammatory attributes of M1 and M2 subsets may enhance or inhibit CD8+ T-cell activity and CTL function.***Hypothesis: Blood monocyte-derived M1 and M2 subsets, and equivalently derived subsets of liver resident macrophages (Kupffer cells and hepatic stellate cells), enhance or inhibit CD8+ T-cell activity, respectively.***SPECIFIC AIMS:***AIM #1: Identify the indirect and direct effects of M1, M2a, M2b and M2c subsets on CD8+ T-cell activity. ***AIM #2: Determine if liver macrophages (Kupffer cells) can be polarized into M1, M2a, 2b and 2c-like subsets and investigate their influence on CD8+ T-cell activity.***AIM #3: Investigate the potential of human stellate cells to be polarized into macrophage subsets and to mediate CD8+ T-cell activity.******RELEVANCE: ***This study will address the fundamental issue of how macrophage subsets influence CD8+ T-cell activity. An added novel component is the characterization of Kupffer cell and hepatic stellate cell subsets according to macrophage phenotypes and their role in adaptive immunity T-cell responses. Linking the innate and adaptive immune systems with these approaches will identify the as yet poorly understood relationship between macrophage subsets and CD8+ T-cells in tolerance and immune response, specifically in the liver.********
背景:*** 先天免疫细胞如巨噬细胞对T细胞应答的协调是适应性免疫的标志。巨噬细胞亚群的细胞因子产生和细胞-细胞接触对CD 4 + T细胞亚群分化的影响已得到充分描述,而它们对CD 8 + T细胞活性和细胞溶解(CTL)功能的控制仍不清楚。最近已经描述了血液来源的巨噬细胞分化为M1、M2 a、2b和2c亚群,建立炎症、免疫调节或组织修复细胞因子环境。此外,组织特异性巨噬细胞在维持免疫耐受和平衡免疫应答和浸润性CD 8 + T细胞的组织破坏作用中的作用仍有待充分描述。例如,最近已经描述了肝脏驻留巨噬细胞(枯否细胞,KC和肝星状细胞,HSC)在非酒精性脂肪肝病中向M1和M2样表型分化,但尚未研究它们对M2 a、2b或2c亚群分化的潜力。M1和M2亚群固有的促炎和抗炎属性可增强或抑制CD 8 + T细胞活性和CTL功能。*假设:血液单核细胞衍生的M1和M2亚群,以及肝脏驻留巨噬细胞(枯否细胞和肝星状细胞)的等效衍生亚群,分别增强或抑制CD 8 + T细胞活性。*具体目标:* 目标#1:确定M1、M2 a、M2 b和M2 c亚群对CD 8 + T细胞活性的间接和直接影响。* AIM#2:确定肝脏巨噬细胞(枯否细胞)是否可以极化为M1、M2 a、2b和2c样亚群,并研究其对CD 8 + T细胞活性的影响。*目的#3:研究人星状细胞极化为巨噬细胞亚群并介导CD 8 + T细胞活性的潜力。******相关性:* 本研究将解决巨噬细胞亚群如何影响CD 8 + T细胞活性的基本问题。增加的新组分是根据巨噬细胞表型表征枯否细胞和肝星状细胞亚群及其在适应性免疫T细胞应答中的作用。将先天性和适应性免疫系统与这些方法联系起来,将确定巨噬细胞亚群和CD 8 + T细胞在耐受性和免疫应答中的关系,特别是在肝脏中。

项目成果

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Crawley, Angela其他文献

Crawley, Angela的其他文献

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{{ truncateString('Crawley, Angela', 18)}}的其他基金

The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity
循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制
  • 批准号:
    RGPIN-2015-05674
  • 财政年份:
    2021
  • 资助金额:
    $ 2.55万
  • 项目类别:
    Discovery Grants Program - Individual
The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity
循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制
  • 批准号:
    RGPIN-2015-05674
  • 财政年份:
    2020
  • 资助金额:
    $ 2.55万
  • 项目类别:
    Discovery Grants Program - Individual
The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity
循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制
  • 批准号:
    RGPIN-2015-05674
  • 财政年份:
    2019
  • 资助金额:
    $ 2.55万
  • 项目类别:
    Discovery Grants Program - Individual
The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity
循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制
  • 批准号:
    RGPIN-2015-05674
  • 财政年份:
    2017
  • 资助金额:
    $ 2.55万
  • 项目类别:
    Discovery Grants Program - Individual
The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity
循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制
  • 批准号:
    RGPIN-2015-05674
  • 财政年份:
    2016
  • 资助金额:
    $ 2.55万
  • 项目类别:
    Discovery Grants Program - Individual
The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity
循环巨噬细胞及其肝脏对应物(枯否细胞和肝星状细胞)改变 CD8 T 细胞活性的机制
  • 批准号:
    RGPIN-2015-05674
  • 财政年份:
    2015
  • 资助金额:
    $ 2.55万
  • 项目类别:
    Discovery Grants Program - Individual

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