Interplay of Regulatory Innate T Cells and Pathogenic T Clonotypes In Dermatitis

皮炎中调节性先天 T 细胞与致病性 T 克隆型的相互作用

基本信息

批准号：
9332774
负责人：
Eric S Huseby
金额：
$ 58.31万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332774
关键词：
Accounting Acute Affect Allergic Animal Model Antigens Asthma Atopic Dermatitis CD4 Positive T Lymphocytes CD8B1 gene Cells Child Chronic Chronic Phase Clone Cells Data Dermal Dermatitis Dermis Developed Countries Developing Countries Development Disease Disease Pathway Effector Cell Employee Strikes Epithelial Event Evolution Extravasation Generations Genes Genetic Homeostasis Human Hyperactive behavior Immune Immune response Impairment Individual Infiltration Inflammation Inflammatory Interleukin-1 Interleukin-13 Interleukin-17 Interleukin-4 Interleukin-5 Interleukin-6 Interleukin-9 Invaded Life Lymphocyte Lymphoid Lymphoid Cell Maps Mediating Modeling Molecular Monitor Mus Mutation Nature Neonatal Neutrophil Infiltration Nomenclature Organ Pathogenicity Phase Phenotype Population Positioning Attribute Production Recruitment Activity Relapse Resolution Rest Role SOX13 gene Seeds Site Skin Stress Surveys Symptoms T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TNF gene TSLP gene Testing Th2 Cells Time Tissues Transgenic Organisms allergic response aryl hydrocarbon receptor ligand commensal microbes cytokine deep sequencing eosinophil fitness fortification interleukin-22 interleukin-23 keratinocyte mast cell mouse model novel pathogen pathogen exposure prevent repaired response skin barrier skin disorder skin hypersensitivity skin lesion γδ T cells

项目摘要

Abstract Atopic Dermatitis (AD) is a T cell hypersensitivity skin disease and is associated with weakened skin barrier. People with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most susceptible individuals do not develop the diseases, suggesting that there exist regulatory immune mechanisms. We have developed an animal model to identify the regulatory immune circuit that prevents AD. Absence of innate IL-17+ γδ T (Tγδ17) cells results in spontaneous AD with all major hallmarks of human AD, placing these cells as the apex regulator of skin homeostasis. In the chronic AD stage, distinct CD4+ T helper effector subsets of constrained clonotypes dominate. Skin Th17 and Th22 cells are commensal bacteria (CB)- dependent, highly restricted in T cell antigen receptor (TCR) repertoire, and some of the clonotypes are extensively expanded in normal and diseased skin. Coincidently, type 2 cytokine secreting innate lymphoid cells 2 (ILC2) expand, which sets up an amplifying autofeedback loop with T cells to chronically inflame the skin. The following model of AD progression will be tested: 1. Regulatory stage: Dermal Tγδ17 cells and αβ T cells survey skin homeostasis and barrier integrity by monitoring dermal APCs. Tγδ17 and Th2 cells seed the skin early in life. Tγδ17 cells, CB and local DCs coordinately promote barrier integrity through crosstalk with keratinocytes. Meanwhile, polyclonal Th2 cells are positioned to induce an allergic response towards invading pathogens. During the colonization of skin by CB, a symbiotic immune response ensues with Vβ4+ CB-specific CD4+ T cells expanding and differentiating into `non-pathogenic' skin resident IL-17+ T cells. 2. Elicitation stage: When Tγδ17 cells are compromised, the barrier is degraded over time with an attendant leakage of CB and enhanced necroptosis, leading to the release of skin antigens that activate Th2 cells, and DAMPs, the most critical being IL-33. In conjunction with TSLP released by keratinocyte under stress, IL-33 drives ILC2 expansion, which further amplifies Th2 cells. Activated ILC2 and Th2 cells, in turn unleash mast cells. Together, excess type 2 cytokine production recruits eosinophils. Some tissue-resident, Th17 cells become activated and promote neutrophil recruitment. 3. Pathogenic stage: During the acute phase, IL-17 release further recruits neutrophils and amplifies the inflammatory cascade that leads to epithelial barrier damage. Inflammation and antigen release from damaged skin activates oligoclonal T cells in the skin dLNs and/or in lesional skin sites. IL-1, IL-6, IL-23, Ahr ligands and TNFα released during inflammation induces skin-resident Th17 cells to expand and acquire a `pathogenic' dual IL-17/22+ phenotypes, whereas the emergent Th22 cells represent an immune countermeasure to repair damaged skin. By mapping central cellular interactions and molecular regulatory network in spontaneous mouse models of AD, the origin of AD and the nature of pathogenic T cells can be understood, paving the way towards identification of T cell skin antigens responsible for AD.

抽象的特应性皮炎 (AD) 是一种 T 细胞过敏性皮肤病，与皮肤屏障减弱有关。与组织屏障健康相关的基因发生突变的人容易患炎症性疾病，但大多数易感个体不会患上这种疾病，这表明存在调节性免疫系统我们开发了一种动物模型来识别预防 AD 的调节性免疫回路。先天性 IL-17+ γδ T (Tγδ17) 细胞的缺失会导致自发性 AD，并具有人类 AD 的所有主要特征，在慢性 AD 阶段，这些细胞作为皮肤稳态的顶端调节器，是独特的 CD4+ T 辅助细胞。受限克隆型的效应子亚群占主导地位的是皮肤 Th17 和 Th22 细胞的共生细菌 (CB)。依赖的，T细胞抗原受体（TCR）库的高度限制，并且一些克隆型是巧合的是，2 型细胞因子分泌先天淋巴细胞。 2 (ILC2) 扩展，与 T 细胞建立一个放大的自动反馈回路，使皮肤长期发炎。将测试以下 AD 进展模型： 1. 调节阶段：真皮 Tγδ17 细胞和 αβ T 细胞调查通过监测生命早期皮肤中的 Tγδ17 和 Th2 细胞来维持皮肤稳态和屏障完整性。 Tγδ17 细胞、CB 和局部 DC 通过与角质形成细胞的相互作用协调促进屏障完整性。同时，多克隆 Th2 细胞可诱导针对入侵病原体的过敏反应。在 CB 定植皮肤期间，Vβ4+ CB 特异性 CD4+ T 细胞会产生共生免疫反应扩增并分化为“非致病性”皮肤驻留 IL-17+ T 细胞 2. 激发阶段：Tγδ17 时。细胞受到损害，屏障随着时间的推移而退化，伴随着CB的泄漏和增强坏死性凋亡，导致皮肤抗原的释放，激活 Th2 细胞和 DAMP，其中最关键的是 IL-33 与压力下角质形成细胞释放的 TSLP 结合，驱动 ILC2 扩增，从而促进 ILC2 的扩增。进一步扩增激活的 ILC2 和 Th2 细胞，进而释放过量的 2 型细胞。细胞因子的产生会招募嗜酸性粒细胞，一些组织驻留的 Th17 细胞被激活并促进。 3. 中性粒细胞募集：在急性期，IL-17 释放进一步募集中性粒细胞。并放大导致上皮屏障损伤的炎症级联反应。受损皮肤的释放会激活皮肤 dLN 和/或病变皮肤部位的寡克隆 T 细胞。炎症期间释放的 IL-23、Ahr 配体和 TNFα 诱导皮肤驻留 Th17 细胞扩张并获得“致病性”双重 IL-17/22+ 表型，而出现的 Th22 细胞代表免疫通过绘制中枢细胞相互作用和分子调节来修复受损皮肤。在自发性 AD 小鼠模型中，AD 的起源和致病性 T 细胞的性质可以通过网络理解，为识别导致 AD 的 T 细胞皮肤抗原铺平了道路。