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

特殊 CD4 T 细胞群对皮肤免疫和组织修复的调节

• 批准号: 9926223
• 负责人: Daniel J Campbell
• 金额: $ 48.57万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926223
• 关键词: Address; Animal Model; Behavior; Blood; CCR8 gene; CD4 Positive T Lymphocytes; CD69 antigen; CD8B1 gene; Cell Differentiation process; Cells; Communities; Cutaneous; Development; Engineering; FOXP3 gene; Fibroblasts; GPR2 gene; Granulocyte-Macrophage Colony-Stimulating Factor; Home environment; Homeostasis; Homing; Human; Immunity; In Vitro; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Integrins; Interleukin-13; Irritants; Lymphocyte antigen; Mediating; Memory; Molecular; Molecular Target; Mus; Normal tissue morphology; Organism; Phenotype; Population; Production; Regulation; Regulatory T-Lymphocyte; Role; Skin; Skin Tissue; Sterility; Structure; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissue Engineering; Tissue Grafts; Tissues; Toxic Environmental Substances; Viral; Work; antimicrobial; antimicrobial peptide; base; cellular targeting; chemokine receptor; combat; cytokine; humanized mouse; innovation; insight; interleukin-22; keratinocyte; macrophage; microorganism; migration; monocyte; mouse model; novel; pathogen; peripheral blood; prevent; response; skin disorder; tissue repair; tissue-repair responses; trafficking; wound; wound healing

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.

项目概要 与其维持屏障完整性和预防感染的功能一致，皮肤是 大量专门的 T 细胞群不仅可以对抗感染，还可以协同工作来帮助 维持正常组织稳态，促进伤口修复。然而，尽管在 了解皮肤免疫、不同皮肤 T 细胞群的特定功能、它们的作用 在维持正常皮肤稳态中的作用以及对皮肤炎症性疾病的贡献仍然存在 不太了解。在这方面，由于基本原理的原因，对动物模型的依赖可能会出现问题。 人类与小鼠皮肤的结构差异，以及皮肤之间缺乏直接对应关系 这些物种中的 T 细胞群。此外，虽然亲肤性 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 T 细胞群的功能关系仍然很差 明白了。 我们在健康受试者的外周血中发现了一个新的 CLA+CD4+ T 细胞群， 表达 CD103 整合素并产生 IL-22、GM-CSF 和 IL-13 的新型细胞因子组合 激活（CD103+CLAhi 细胞）。有趣的是，这种细胞因子组合也是由表型产生的 皮肤本身的表皮CD103 CLA CD69 TRM 类似。基于IL-22的促进能力 +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分化为“替代激活”细胞 促进组织修复，我们假设血液中的 CD103+CLAhi T 细胞代表再循环 CD103+CLAhi TRM 的一部分，并且这些细胞有助于协调宿主保护和伤口 皮肤组织损伤后的愈合反应。因此，这些细胞有可能成为 通过治疗手段促进无菌伤口愈合并优化伤口的发育和功能 工程组织移植物。  在本提案中，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 CD103+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期间的功能。