Regulation of cutaneous immunity and tissue-repair by a specialized population of CD4+ T cells

项目摘要 与其保持屏障完整性和预防感染的功能一致，皮肤是 专门的T细胞群的数量，不仅可以对抗感染，还可以协同工作，帮助 维持正常组织动态平衡，促进伤口修复。然而，尽管在以下方面取得了重大进展 了解皮肤免疫，不同群体皮肤T细胞的特定功能，他们 在维持正常皮肤动态平衡方面的作用，以及对皮肤炎症性疾病的贡献 人们对此知之甚少。在这方面，依赖动物模型可能是有问题的，因为 人类和小鼠皮肤的结构差异，以及皮肤之间缺乏直接的对应关系 这些物种中的T细胞群。此外，尽管嗜皮性T细胞可以很容易地在 外周血基于皮肤淋巴细胞抗原(CLA)的表达，发育和 血液中这些细胞与皮肤中不同数量的T细胞的功能关系仍然很差 明白了。 我们已经在健康受试者的外周血中发现了一种新的CLA CD4T细胞群 表达CD103整合素并产生IL-22、GM-CSF和IL-13的新细胞因子组合 激活(CD103 CLAHI细胞)。有趣的是，这种细胞因子组合也是由表型 类似于表皮CD103、CLA、CD69、TRM在皮肤本身。基于IL-22促进的能力 嗨 角质形成细胞的增殖、迁移和抗菌肽的产生以及GM-CSF和IL-13的作用 成纤维细胞，并介导单核细胞和巨噬细胞向“交替激活”细胞的分化 促进组织修复，我们假设血液中的CD103CLAHI T细胞代表着循环 CD103 CLAHI TRM的一部分，这些细胞有助于协调宿主保护和创伤 皮肤组织损伤后的愈合反应。因此，这些细胞有可能成为 以治疗的方式促进无菌伤口的愈合并优化其发展和功能 工程组织移植物。在这个提案中，我们将使用体外分析和创新的人源化小鼠 验证这些假说的模型，评估CD103CLAHI的发育起源和运输行为 并确定它们在皮肤组织修复反应中的功能。

Project Summary Consistent with its functions in maintaining barrier integrity and preventing infection, the skin is home to a number of specialized T cell populations that not only combat infection but also work in concert to help maintain normal tissue homeostasis and promote wound repair. However, despite significant advances in understanding cutaneous immunity, the specific functions of different populations of cutaneous T cells, their roles in maintaining normal skin homeostasis, and contributions to inflammatory diseases of the skin remain poorly understood. In this respect, reliance on animal models can be problematic due to fundamental structural differences in the skin in humans vs. mice, and a lack of direct correspondence between cutaneous T cell populations in these species. Additionally, although skin-tropic T cells can be readily identified in peripheral blood based on their expression of the cutaneous lymphocyte antigen (CLA), the developmental and functional relationship of these cells in the blood with the different populations of T cells in the skin is still poorly understood. We have identified a novel population of CLA+CD4+ T cells in the peripheral blood of healthy subjects that expresses the CD103 integrin and produces the novel cytokine combination of IL-22, GM-CSF and IL-13 upon activation (CD103+CLAhi cells). Interestingly, this cytokine combination is also produced by phenotypically similar epidermal CD103 CLA CD69 TRM in the skin itself. Based on the ability of IL-22 to promote + hi + keratinocyte proliferation, migration and production of antimicrobial peptides, and GM-CSF and IL-13 to act on fibroblasts, and to mediate the differentiation of monocytes and macrophages into `alternatively activated' cells that promote tissue repair, we hypothesize CD103+CLAhi T cells in the blood represent a recirculating fraction of CD103+CLAhi TRM, and that these cells help coordinate the host-protective and wound healing responses following tissue damage in the skin. As such, these cells have the potential to be manipulated therapeutically to promote sterile wound healing and to optimize the development and function of engineered tissue grafts.  In this proposal, we will use in vitro analyses and innovative humanized mouse models to test these hypotheses, assessing the developmental origins and trafficking behavior of CD103+CLAhi cells and determining their function during cutaneous tissue-repair responses.