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

项目摘要 患有特应性皮炎的个体具有增加的严重复发性和播散性病毒感染的风险。 感染，但原因尚不清楚。防御局部感染依赖于组织驻留记忆CD 8 + T 细胞（TRM），提供快速防御入侵的病原体。我们假设CD 8 + TRM的损伤 导致特应性皮炎患者严重感染。我们的初步数据表明，IL-4 对抗TGF-β诱导的CD 8 + TRM受体表达，这是外周血中持续存在所必需的。 组织中与此同时，体内研究表明，CD 8 + T细胞暴露于IL-4会降低其积累 在发炎的皮肤里基于这些初步的数据，我们假设IL-4可以阻止TGF-β介导的 信号传导和/或改变CD 8 + T细胞中TGF-β靶基因周围的染色质景观， 改变的CD 8 + T细胞表型。我们预测，这些表型变化阻碍了长期的 皮肤CD 8 + TRM的持续存在和TRM介导的对局部病毒感染的防御受损。我们将测试 i）使用过敏性湿疹的小鼠模型来分析局部Th 2-型 炎症对CD 8 + TRM持续性和对HSV感染的保护作用ii）分析Th 2 iii）研究IL-4对TGF-β 1表达的影响， bR信号传导和CD 8 + T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.