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

项目摘要 与其维持屏障完整性和预防感染的功能一致，皮肤是 一些专门的T细胞群，不仅对抗感染，而且还协同工作，帮助 维持正常组织的稳态并促进伤口修复。然而，尽管取得了重大进展， 了解皮肤免疫，皮肤T细胞的不同群体的特定功能， 在维持正常皮肤稳态中的作用以及对皮肤炎性疾病的贡献仍然存在 不太了解。在这方面，依赖于动物模型可能是有问题的，因为基本的 人类与小鼠皮肤的结构差异，以及皮肤与皮肤之间缺乏直接对应关系， 这些物种中的T细胞群。此外，虽然皮肤嗜性T细胞可以很容易地鉴定， 外周血基于其皮肤淋巴细胞抗原（CLA）的表达，发育和 血液中的这些细胞与皮肤中的不同T细胞群的功能关系仍然很差 明白 我们已经在健康受试者的外周血中鉴定了一种新的CLA+ CD 4 + T细胞群体， 表达CD 103整联蛋白，并在表达后产生IL-22、GM-CSF和IL-13的新型细胞因子组合。 活化（CD 103 +CLAhi细胞）。有趣的是，这种细胞因子组合也是由表型 类似的表皮CD 103 CLA CD 69 TRM在皮肤本身。基于IL-22促进 + Hi + 角质形成细胞增殖、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分化为“交替激活”细胞 促进组织修复，我们假设血液中的CD 103 +CLAhi T细胞代表了一种循环， 这些细胞有助于协调宿主保护性和创伤修复性T细胞。 皮肤组织损伤后的愈合反应。因此，这些细胞有可能成为 在治疗上进行操作，以促进无菌伤口愈合，并优化 工程组织移植物 在这项提案中，我们将使用体外分析和创新的人源化小鼠， 模型来检验这些假设，评估CD 103 +CLAhi的发育起源和贩运行为， 细胞，并确定它们在皮肤组织修复反应过程中的功能。

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.