Effect of Th2-type microenvironment on CD8 TRM-mediated protection from infection

项目摘要摘要 患有特应性皮炎的个体增加了严重复发和传播病毒的风险。 感染，但原因尚不清楚。对局部感染的防御依赖于组织驻留记忆CD8 T 提供快速防御入侵病原体的细胞(TRM)。我们假设CD8TRM的损伤 会导致特应性皮炎患者的严重感染。我们的初步数据显示，IL-4 拮抗转化生长因子-b诱导外周血中持续存在的CD8TRM受体表达 纸巾。与此同时，体内研究表明，CD8T细胞暴露于IL-4会减少它们的积聚 在发炎的皮肤里。根据这些初步数据，我们假设IL-4阻止了转化生长因子-b介导的 信号传递和/或改变CD8T细胞中转化生长因子-b靶基因周围的染色质景观，结果 CD8T细胞表型改变。我们预测，这些表型变化阻碍了长期的 皮肤CD8 TRM持续存在，并削弱TRM介导的局部病毒感染防御。我们将测试 这些假设由i)使用过敏性湿疹的小鼠模型来分析局部Th2型的影响 炎症对CD8TRM持久性的影响及对HSV感染的保护作用II)Th2的作用分析 细胞因子对人CD8TRM表型和功能的影响，以及III)研究IL-4对转化生长因子-4的影响 BR信号和CD8T细胞的染色质景观。

Project Summary Abstract Individuals suffering from atopic dermatitis have increased risk for serious recurrent and disseminated viral infections, but the cause is unclear. Defense against local infections relies on tissue resident memory CD8+ T cells (TRM) that deliver rapid defense against invading pathogens. We hypothesize that impairment of CD8+ TRM contributes to severe infection in patients with atopic dermatitis. Our preliminary data demonstrate that IL-4 counters TGF-b-induced expression of CD8+ TRM receptors that are required for persistence within peripheral tissues. In parallel, in vivo studies reveal that exposure of CD8+ T cells to IL-4 decreases their accumulation within inflamed skin. Based on these preliminary data, we hypothesize that IL-4 prevents TGF-b-mediated signaling and/or changes the chromatin landscape surrounding TGF-b target genes in CD8+ T cells, resulting in an altered CD8+ T cell phenotype. We predict that these phenotypic changes impede the long-term persistence of cutaneous CD8+ TRM and impair TRM-mediated defense against local viral infection. We will test these hypotheses by i) using mouse models of allergic eczema to analyze the impact of local Th2-type inflammation on CD8+ TRM persistence and protection from HSV infection ii) analyzing the effect of Th2 cytokines on the phenotype and function of human CD8+ TRM, and iii) investigating the impact of IL-4 on TGF- bR signaling and the chromatin landscape of CD8+ T cells.