Commensal-specific T cell function in skin wound repair

项目摘要 我们对免疫力的理解很大程度上源于病原微生物感染的模型。但 绝大多数的微生物-免疫接触是作为与肠道微生物群的共生关系发生的。 近年来，肿瘤特异性T细胞对宿主生理的贡献受到了广泛关注。 这些特定于微生物的反应不仅控制了微生物群的遏制， 通过对先天细胞和上皮细胞的作用进行防御。角质形成细胞的局部调节， T细胞也有助于皮肤损伤后的组织修复。相反地，对大肠杆菌的异常免疫 已经提出微生物是屏障组织病理学的基础，包括特应性皮炎， 炎症性肠病对肿瘤特异性T细胞特性和功能的认识 因此，免疫应答是健康和疾病中组织免疫研究的基础。我们的长期目标是 更好地了解组织特异性T细胞反应如何有助于屏障组织的稳态， 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。我们提出这项工作的理由是，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，直肠特异性T细胞是 皮肤组织的哨兵，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。在这个建议中，我们将重点放在两个机制，转录后调控 IL-5和IL-13细胞因子的产生，通过RNA结合蛋白和诱导 综合应激反应基于强有力的初步数据，我们将测试三个具体目标：（1）了解 关键的近端和远端IL-18 R信号通路，触发平衡的2型免疫，在膀胱特异性 CD 8 + T细胞。我们最近发现，IL-18直接作用于CD 8 + T细胞可以触发快速产生IL-18。 IL-5和IL-13。我们将检验IL-18 R特有的通路，而不是其他IL-1 R家族成员的通路， 触发膀胱特异性CD 8 + T细胞中稳定的2型免疫。(2)确定未翻译的角色 IL 15和IL 13 mRNA的非编码区（UTR）在卵巢特异性CD 8 + T细胞中平衡的2型免疫中的作用。我们有 在IL 5和IL 13 mRNA的UTR中鉴定了多个RNA结合蛋白基序。我们将测试 这些调节元件在膀胱特异性CD 8 + T细胞中平衡2型免疫。(3)了解 整合应激反应对IL 5和IL 13 mRNA转录后调节的贡献， 组织特异性CD 8 + T细胞及其对伤口修复的贡献我们的方法是创新的，因为它 研究了免疫系统特异性T细胞应答的新机制。拟议工作 意义重大，因为它将为企业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点 在慢性非解决伤口和皮肤感染的条件下。

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.