Commensal-specific T cell function in skin wound repair

皮肤伤口修复中的共生特异性 T 细胞功能

• 批准号: 10337339
• 负责人: Oliver James Harrison
• 金额: $ 58.73万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337339
• 关键词: Adaptive Immune System; Atopic Dermatitis; Attention; Autoimmune Diseases; Body Surface; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Chronic; Communication; Containment; Cues; Cutaneous; Data; Development; Disease; Distal; Epithelial Cells; Family member; GATA3 gene; Gene Expression Profile; Goals; Grant; Health; Homeostasis; Host Defense; Human; Hybrids; Immune; Immune response; Immune system; Immunity; Infection; Infection prevention; Infectious Skin Diseases; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Interleukin-13; Interleukin-17; Interleukin-18; Interleukin-5; Mediating; Memory; Messenger RNA; MicroRNAs; Mission; Modeling; Molecular Target; Mus; PPBP gene; Pathology; Pathway interactions; Peptide/MHC Complex; Pharmacology; Physiology; Play; Population; Post-Transcriptional Regulation; Production; Property; Protein Binding Domain; Proteins; Psoriasis; RNA-Binding Proteins; Reagent; Regulatory Element; Reporter; Research; Role; Sentinel; Signal Pathway; Skin; Skin Tissue; Skin colonization; Skin injury; Staphylococcus epidermidis; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Translating; Translations; United States National Institutes of Health; Untranslated Regions; Work; Wound Infection; antimicrobial; base; biological adaptation to stress; commensal microbes; cytokine; genetic manipulation; in vivo; injury and repair; innovation; insight; keratinocyte; microbial; microbiota; mouse model; mutualism; novel; novel therapeutic intervention; pathogen; pathogenic microbe; repaired; resident commensals; response; skin barrier; skin wound; stem; targeted treatment; tissue injury; tissue repair; tool; transcriptome; wound healing

PROJECT SUMMARY Our understanding of immunity largely stems from models of infection with pathogenic microbes. However, the vast majority of microbial-immune encounters occur as a symbiotic relationship with the commensal microbiota. Recently, the contribution of commensal-specific T cells to host physiology has received significant attention. These commensal-specific responses not only control microbiota containment but also promote antimicrobial defenses via their action on both innate and epithelial cells. Local tuning of keratinocytes by commensal-specific T cells also contributes to tissue repair following skin injury. Conversely, aberrant immunity to commensal microbes has been proposed to underlie pathologies of barrier tissues, including atopic dermatitis and inflammatory bowel disease. A better understanding of the properties and functions of commensal-specific T cell responses is therefore fundamental to studies of tissue immunity in health and disease. Our long-term goal is to better understand how commensal-specific T cell responses contribute to barrier tissue homeostasis, and the objective in this application is to investigate the mechanisms regulating cytokine production during skin injury and wound repair. Our rationale for the proposed work is that uncovering these mechanisms has the potential to translate into new therapeutic approaches. Our central hypothesis is that commensal-specific T cells are sentinels of the skin tissue and contribute to wound repair through rapid production of type-2 cytokines in response to tissue injury. In this proposal, we will focus on two mechanisms, the post-transcriptional regulation of IL-5 and IL-13 cytokine production by commensal-specific T through RNA-binding proteins and induction of the integrated stress response. Based on strong preliminary data, we will test three specific aims: (1) Understand the key proximal and distal IL-18R-signaling pathways that trigger poised type-2 immunity in commensal-specific CD8+ T cells. We have recently found that IL-18 acting directly on CD8+ T cells can trigger rapid production of IL-5 and IL-13. We will test the hypothesis that pathways unique to IL-18R, but not other IL-1R family members triggers poised type-2 immunity in commensal-specific CD8+ T cells. (2) Determine the role of Untranslated regions (UTR) of Il5 and Il13 mRNA in poised type-2 immunity in commensal-specific CD8+ T cells. We have identified multiple RNA-binding protein motifs in the UTR of Il5 and Il13 mRNA. We will test the contribution of these regulatory elements to poised type-2 immunity in commensal-specific CD8+ T cells. (3) Understand the contribution of the integrated stress response to post-transcriptional regulation of Il5 and Il13 mRNA in commensal-specific CD8+ T cells and the contribution to wound repair. Our approach is innovative as it investigates new mechanisms of immunity unique to commensal-specific T cell responses. The proposed work is significant because it will establish new insights into the interaction and communication between commensal microbes and immune cells in the skin microenvironment and identify potential targets for therapeutic intervention in conditions of chronic non-resolving wounds and skin infection.

项目总结 我们对免疫的理解在很大程度上源于病原微生物感染的模型。然而， 绝大多数微生物-免疫接触是作为与共生微生物区系的共生关系发生的。 近年来，共生特异性T细胞对宿主生理的贡献受到了广泛的关注。 这些共生特异性反应不仅控制微生物区系的控制，而且还促进抗菌素的产生。 通过对固有细胞和上皮细胞的作用来防御。角质形成细胞的共面特异性局部调谐 T细胞也有助于皮肤损伤后的组织修复。相反，对共生的异常免疫 微生物被认为是屏障组织病理的基础，包括特应性皮炎和 炎症性肠病。更好地了解共生体特异性T细胞的特性和功能 因此，对健康和疾病中的组织免疫的研究，反应是基本的。我们的长期目标是 更好地了解共生特异性T细胞反应如何有助于屏障组织的动态平衡，以及 目的探讨皮肤损伤时细胞因子产生的调控机制。 和伤口修复。我们提议的工作的基本原理是，揭示这些机制有可能 转化为新的治疗方法。我们的中心假设是共生体特异性T细胞是 皮肤组织的前哨，并通过快速产生2型细胞因子促进伤口修复 对组织损伤的反应。在这个提案中，我们将重点讨论两个机制，转录后调控 共系膜特异性T细胞通过RNA结合蛋白产生IL-5和IL-13细胞因子及其诱导 综合应激反应。基于强大的初步数据，我们将测试三个具体目标：(1)了解 在共生特异性中触发稳定的2型免疫的关键的近端和远端IL-18R信号通路 CD8+T细胞。我们最近发现，IL-18直接作用于CD8+T细胞可以触发快速产生 IL-5和IL-13。我们将检验这一假设，即IL-18R独有的通路，而不是其他IL-1R家族成员 在共生特异性CD8+T细胞中触发稳定的2型免疫。(2)确定未翻译的角色 共系膜特异性CD8+T细胞中稳定的2型免疫中IL5和IL13的区域(UTR)。我们有 在IL5和IL13的非编码区中发现了多个RNA结合蛋白基序。我们将测试以下方面的贡献 这些调节元件稳定在共生特异性CD8+T细胞中的2型免疫。(3)了解 整合应激反应对白介素5和白介素13基因转录后调控的作用 共膜特异性CD8+T细胞及其在伤口修复中的作用。我们的方法是创新的，因为 研究共生特异性T细胞反应特有的免疫新机制。拟议中的工作 具有重要意义，因为它将为共生之间的互动和沟通建立新的见解 皮肤微环境中的微生物和免疫细胞，并确定潜在的治疗干预目标 在慢性未愈合伤口和皮肤感染的情况下。