Effect of allergic asthma on CD8+ TRM-mediated protection from infection

过敏性哮喘对 CD8 TRM 介导的感染保护作用的影响

• 批准号: 10495217
• 负责人: SHANNON K BROMLEY
• 金额: $ 24.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495217
• 关键词: Affect; Allergic; Allergic Disease; Anti-Bacterial Agents; Asthma; Atopic Dermatitis; Bacterial Genes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Child; Cytokine Signaling; Data; Disease; Environment; Exposure to; Extrinsic asthma; Focal Infection; Goals; Immune; Immunity; Impairment; Individual; Infection; Inflammation; Inflammatory; Influenza; Interferons; Interleukin-13; Interleukin-4; Investigation; Laboratories; Leukocytes; Lung; Lung infections; Measures; Mediating; Memory; Mus; Patients; Peripheral; Phenotype; Predisposition; Pyroglyphidae; Recurrence; Regulation; Respiratory Tract Infections; Risk; Role; Signal Transduction; Skin; Testing; Time; Tissues; Viral; Virus; Virus Diseases; Wild Type Mouse; adhesion receptor; antigen challenge; asthma exacerbation; asthmatic; asthmatic patient; base; cytokine; improved; in vivo; influenza infection; inhibitor; mouse model; neutralizing antibody; novel; novel therapeutics; pathogen; prevent; receptor; recruit; respiratory; transcription factor; tumor

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.

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，CD8+TRM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-- CD8+TRM持续存在所需的黏附受体CD49a和CD103的诱导表达 在外周组织内。同时，体内研究表明，CD8+T细胞暴露于IL-4会降低 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CD8+TRM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CD8+TRM介导的流感保护性免疫的影响