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

基本信息

批准号：
10181406
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
项目类别：
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/10181406
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

项目摘要

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.

项目摘要我们对免疫力的理解主要源于致病微生物的感染模型。但是，绝大多数微生物 - 免疫遇到的发生是与共生微生物群的共生关系。最近，共生特异性T细胞对宿主生理的贡献受到了极大的关注。这些共同特异性反应不仅控制微生物群的遏制，还可以促进抗菌素通过对先天细胞和上皮细胞的作用进行防御。通过特定于共生的角色细胞对角质形成细胞进行局部调整 T细胞还有助于皮肤损伤后的组织修复。相反，对共生的异常免疫已提出微生物是障碍组织的病理学的基础，包括特应性皮炎和炎症性肠病。更好地理解共生特异性T细胞的特性和功能因此，反应是健康和疾病中组织免疫研究的基础。我们的长期目标是更好地了解共生特异性的T细胞反应如何有助于屏障组织稳态，并如何影响该应用中的目的是研究调节皮肤损伤过程中细胞因子产生的机制和伤口修复。我们对拟议工作的理由是，发现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特异性的T细胞是皮肤组织的前哨，并通过快速产生2型细胞因子在对组织损伤的反应。在此提案中，我们将重点介绍两种机制，即转录后法规通过RNA结合蛋白通过共生特异性T的IL-5和IL-13细胞因子的产生，并诱导综合应力反应。根据强大的初步数据，我们将测试三个特定目的：（1）了解关键的近端和远端IL-18R信号途径，这些途径触发了共生特异性的2型免疫力 CD8+ T细胞。我们最近发现，直接作用在CD8+ T细胞上的IL-18可以触发快速产生 IL-5和IL-13。我们将检验以下假设：IL-18R独有的途径，而不是其他IL-1R家族成员在共生特异性CD8+ T细胞中触发了2型免疫。（2）确定未翻译的作用在共生特异性CD8+ T细胞中，IL5和IL13 mRNA的IL5和IL13 mRNA区域（UTR）。我们有在IL5和IL13 mRNA的UTR中鉴定出多个RNA结合蛋白基序。我们将测试这些调节性元素涉及共同特异性CD8+ T细胞中固定的2型免疫力。（3）了解综合应力反应对IL5和IL13 mRNA转录后调节的贡献共生特异性的CD8+ T细胞以及对伤口修复的贡献。我们的方法是创新的研究了共同特异性T细胞反应独有的免疫机制。拟议的工作之所以重要，是因为它将对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，并确定治疗干预的潜在靶标在慢性非分解伤口和皮肤感染的情况下。