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中文摘要
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患有局部Th2型炎症性疾病的人,包括过敏性哮喘,风险增加 对于严重的病毒感染,但原因尚不清楚。防御局部感染有赖于组织 常驻记忆CD8 T细胞(TRM),驻留在外周组织中,提供快速防御 病原体和肿瘤。在抗原攻击后,CD8TRM分泌细胞因子激活固有细胞, 诱导抗病毒和抗细菌基因的表达,并招募循环白细胞用于病原体控制。 鉴于它们在宿主保护中的核心作用,我们假设CD8 TRM的损害有助于严重 特应性疾病患者的感染情况。我们的初步数据表明,IL-4可以唯一地阻止转化生长因子-- CD8TRM维持所需的黏附受体CD49a和CD103的诱导表达 在外周组织内。同时,体内研究表明,CD8T细胞暴露于IL-4会降低两者 CD103的表达及其在皮肤中的蓄积。根据这些初步数据,我们 建议使用过敏性哮喘的小鼠模型来扩展这些研究,以测试Th2 细胞因子损害肺CD8 TRM的形成、持久性和对呼吸道感染的防御。具体来说, 我们建议:1)确定Th2型微环境对肺CD8TRM的影响 对已建立的CD8 TRM的形成/持久性以及表型稳定性的影响;以及2)决定 IL-4对肺CD8TRM介导的流感保护性免疫的影响
英文摘要
Individuals suffering from local Th2-type inflammatory diseases, including allergic asthma have increased risk for serious viral infections, but the cause is unclear. Defense against local infections relies on tissue resident memory CD8+ T cells (TRM) that reside within peripheral tissues and deliver rapid defense against pathogens and tumors. Following antigen challenge, CD8+ TRM secrete cytokines that activate innate cells, induce expression of anti-viral and anti-bacterial genes, and recruit circulating leukocytes for pathogen control. Given their central role in host protection, we hypothesize that impairment of CD8+ TRM contributes to severe infection in patients with atopic diseases. Our preliminary data demonstrate that IL-4 uniquely prevents TGF-- induced expression of the adhesion receptors CD49a and CD103 that are required for CD8+ TRM persistence within peripheral tissues. In parallel, in vivo studies reveal that exposure of CD8+ T cells to IL-4 decreases both their expression of CD103 as well as their accumulation within skin. Based on these preliminary data, we propose to extend these studies using a mouse model of allergic asthma to test the novel hypothesis that Th2 cytokines impair lung CD8+ TRM formation, persistence and defense against respiratory infection. Specifically, we propose to: 1) Determine the impact of a Th2-type microenvironment on lung CD8+ TRM formation/persistence, as well as on the phenotypic stability of established CD8+ TRM; and 2) Determine the consequence of IL-4 on lung CD8+ TRM-mediated protective immunity to influenza infection.
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Effect of Th2-type microenvironment on CD8 TRM-mediated protection from infection
  • 批准号:
    10624943
  • 项目类别:
  • 资助金额:
    $57.93万
  • 财政年份:
    2022
  • 负责人:
    SHANNON K BROMLEY
  • 依托单位:
Effect of allergic asthma on CD8+ TRM-mediated protection from infection
  • 批准号:
    10495217
  • 项目类别:
  • 资助金额:
    $24.52万
  • 财政年份:
    2021
  • 负责人:
    SHANNON K BROMLEY
  • 依托单位:
Mechanisms of CD49a Expression and Resident Memory T Cell Formation in Skin.
  • 批准号:
    9302659
  • 项目类别:
  • 资助金额:
    $41.69万
  • 财政年份:
    2016
  • 负责人:
    SHANNON K BROMLEY
  • 依托单位:
Bromley Pilot and Feasibility Project
  • 批准号:
    7393279
  • 项目类别:
  • 资助金额:
    $4.15万
  • 财政年份:
    2007
  • 负责人:
    SHANNON K BROMLEY
  • 依托单位:
海外基金