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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要摘要患有特应性皮炎的个体患严重复发性和传播性病毒的风险增加感染，但原因尚不清楚。防御局部感染依赖于组织驻留记忆 CD8+ T 细胞（TRM），可快速防御入侵的病原体。我们假设 CD8+ TRM 受损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-b 诱导的 CD8+ TRM 受体表达，这是外周血中持续存在所必需的组织。与此同时，体内研究表明，CD8+ T 细胞暴露于 IL-4 会减少其积累在发炎的皮肤内。基于这些初步数据，我们假设 IL-4 可以阻止 TGF-b 介导的信号转导和/或改变 CD8+ T 细胞中 TGF-b 靶基因周围的染色质景观，从而 CD8+ T 细胞表型发生改变。我们预测这些表型变化会阻碍长期皮肤 CD8+ TRM 的持续存在并削弱 TRM 介导的针对局部病毒感染的防御。我们将测试这些假设通过 i) 使用过敏性湿疹小鼠模型来分析局部 Th2 型的影响炎症对 CD8+ TRM 持久性和 HSV 感染保护作用 ii) 分析 Th2 的影响细胞因子对人 CD8+ TRM 表型和功能的影响，以及 iii) 研究 IL-4 对 TGF- bR 信号传导和 CD8+ T 细胞的染色质景观。