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

Th2型微环境对CD8 TRM介导的感染保护作用的影响

• 批准号: 10624943
• 负责人: SHANNON K BROMLEY
• 金额: $ 57.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-19 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624943
• 关键词: ATAC-seq; Adult; Allergic Disease; Anti-Bacterial Agents; Atopic Dermatitis; Bacterial Genes; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chromatin; Cutaneous; Data; Disease; Eczema; Eczema Herpeticum; Eczema Vaccinatum; Environment; Exposure to; Extrinsic asthma; Focal Infection; Gene Expression; Genes; Goals; Herpes Simplex Infections; Human; Immune response; Impairment; Individual; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Integrins; Interleukin-13; Interleukin-4; Intestines; Invaded; Leukocytes; Lung; Maintenance; Malignant Neoplasms; Measures; Mediating; Memory; Morbidity - disease rate; Mus; Nuclear Translocation; Patients; Peripheral; Phenotype; Phosphorylation; Predisposition; Proliferating; Psoriasis; Recurrence; Risk; Role; Sampling; Signal Transduction; Simplexvirus; Skin; Testing; Tissues; Transforming Growth Factor beta; Vaccinia virus; Viral; Virus Diseases; Virus Replication; Wild Type Mouse; antigen challenge; cytokine; cytotoxic; effector T cell; immune function; improved; in vivo; inhibitor; mortality; mouse model; neutralizing antibody; novel therapeutics; pathogen; prevent; protein expression; receptor; recruit; response; transcription factor; treatment effect; tumor

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.

项目摘要摘要 患有特应性皮炎的人增加了严重复发和传播病毒的风险 感染，但原因尚不清楚。针对局部感染的防御依赖于组织居民记忆CD8+ T 细胞（TRM）可为入侵病原体提供快速防御。我们假设CD8+ TRM的损害 特征性皮炎患者的严重感染。我们的初步数据表明IL-4 计数器TGF-B诱导的CD8+ TRM受体的表达，这是周围持续性所必需的 组织。同时，体内研究表明，CD8+ T细胞暴露于IL-4会降低其积累 在发炎的皮肤内。基于这些初步数据，我们假设IL-4阻止了TGF-B介导的 信号传导和/或改变CD8+ T细胞中TGF-B靶基因周围的染色质景观，从而 在改变的CD8+ T细胞表型中。我们预测这些表型变化会妨碍长期 皮肤CD8+ TRM的持久性并损害了TRM介导的防御局部病毒感染。我们将测试 这些假设i）使用过敏性湿疹的小鼠模型分析局部Th2型的影响 CD8+ TRM持续性和免受HSV感染的保护症的炎症ii）分析Th2的作用 关于人CD8+ TRM的表型和功能的细胞因子，以及研究IL-4对TGF-的影响 CD8+ T细胞的BR信号传导和染色质景观。