Lung leukocytes promote alveolar epithelial regeneration after severe injury

项目摘要/摘要 人们越来越认识到，非淋巴组织中的淋巴细胞具有独特的效应。 超越其在抗病原体和抗肿瘤免疫方面的作用的计划。这种非免疫功能， 包括调节代谢动态平衡和组织修复，突出免疫学的多样性 能够以特定于组织的方式详细描述以修改生理和发育参数的信号 在给定的利基范围内。为了实现这些不同的调节作用，组织定位的白细胞与 特殊的非淋巴样细胞，定义器官的功能，触发利基特异性效应程序 对组织微环境中的扰动的反应。为了支持这种机制，最近描述了一种 肺调节性T(Treg)细胞群在组织保护中发挥着明显的作用。 流感病毒感染引起小鼠急性肺损伤的早期阶段。通过他们制作的 表皮生长因子受体(EGFR)配体，双调节蛋白，这些Treg细胞支持上皮屏障 再生和保护肺功能。尽管这些发现揭示了一个重要的和以前的 Treg细胞来源的双调节蛋白的作用未知，双调节蛋白如何影响肺的机制细节 修复工作仍未确定。初步研究表明，在应对由其他因素引起的肺损伤时 在损伤性刺激下，除调节性T细胞外的其他白细胞群可产生双调节素。进一步 检查表明，产生双调节素的白细胞可能通过以下途径引导肺泡上皮再生 与特定的肺间充质和上皮干/祖细胞群体相互作用 修复过程的离散步骤。为此，这项提案的主要目标是：1)将 产生双调节素的肺白细胞与居留间充质和上皮细胞的相互作用 干细胞/祖细胞，2)确定这些相互作用的分子基础，并确定它们的相对意义 用于恢复正常的肺功能，以及3)确定这些细胞相互作用如何受到严重程度的影响 或破坏性刺激的类型。这个项目的成功完成将使我们更好地理解 组织特异性免疫反应在指导组织再生和支持未来发展中的作用 寻求刺激这些过程以治疗肺部疾病和恢复正常器官动态平衡的策略。

PROJECT SUMMARY/ABSTRACT It has become increasingly appreciated that lymphocytes within non-lymphoid tissues exhibit unique effector programs that extend beyond their roles in anti-pathogen and anti-tumor immunity. Such non-immune functions, including the regulation of metabolic homeostasis and tissue repair, highlight the diversity of immunological signals that can be elaborated in a tissue-specific manner to modify physiological and developmental parameters within a given niche. To achieve these diverse regulatory roles, tissue-localized leukocytes interact with specialized non-lymphoid cells that define the organ’s function, triggering niche-specific effector programs in response to perturbations within the tissue microenvironment. In support of this mechanism, a recently described population of lung regulatory T (Treg) cells were shown to play a pronounced tissue-protective role during the early stages of acute lung injury caused by influenza virus infection in mice. Through their production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, these Treg cells support epithelial barrier regeneration and preserve lung function. Although these findings uncovered an important and previously unknown role for Treg cell–derived amphiregulin, the mechanistic details of how amphiregulin influences lung repair remained undetermined. Preliminary studies indicate that in response to lung injury caused by other damaging stimuli, infiltrating leukocyte populations other than regulatory T cells produce amphiregulin. Further inspection has suggested that amphiregulin-producing leukocytes may guide alveolar epithelial regeneration by interacting with specific lung mesenchymal and epithelial stem/progenitor cell populations that orchestrate discrete steps of the repair process. To this end, the major goals of this proposal are to 1) characterize interactions between amphiregulin-producing lung leukocytes and resident mesenchymal and epithelial stem/progenitor cells, 2) identify the molecular basis of these interactions and define their relative significance for restoring normal lung function, and 3) determine how these cellular interactions are influenced by the severity or type of damaging stimuli. Successful completion of this project will broaden our understanding of the role of tissue-specific immune responses in directing tissue regeneration and support the development of future strategies that seek to stimulate these processes to treat lung disease and restore normal organ homeostasis.