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: 9384627
• 负责人: Daniel J Campbell
• 金额: $ 50.32万
• 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/9384627
• 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; Symbiosis; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissue Engineering; Tissue Grafts; Tissues; Toxic Environmental Substances; Viral; Work; Wound Healing; 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; trafficking

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.

项目摘要 与其在保持屏障完整性和防止感染方面的功能一致，皮肤是一个家园 不仅战斗感染，而且共同努力的专业T细胞群体数量 保持正常的组织体内稳态并促进伤口修复。但是，理想的显着进步 了解皮肤免疫力，皮肤T细胞不同种群的特定功能，它们 维持正常皮肤稳态的作用，以及对皮肤炎症性疾病的贡献 理解不佳。在这方面，由于基本 人类皮肤与小鼠的结构差异，皮肤之间缺乏直接对应关系 这些物种中的T细胞群体。此外，尽管可以在 外周血根据皮肤淋巴细胞抗原（CLA）的表达，发育和 这些细胞在血液中与皮肤中T细胞不同种群的功能关系仍然很差 理解。 我们已经确定了在健康受试者的外周血中的新型CLA+ CD4+ T细胞， 表达CD103整联蛋白，并在IL-22，GM-CSF和IL-13上产生新的细胞因子组合 激活（CD103+Clahi细胞）。有趣的是，这种细胞因子组合也由表型产生 皮肤本身中的类似表皮CD103 CLA CD69 TRM。基于IL-22促进的能力 + HI + 角质形成细胞增殖，抗菌胡椒的迁移和生产，以及GM-CSF和IL-13，以作用于 成纤维细胞，并介导单核细胞和巨噬细胞的分化为“替代激活”细胞 为了促进组织修复，我们假设血液中的CD103+Clahi T细胞代表了再循环 CD103+Clahi TRM的一部分，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 从理论上操纵以促进无菌伤口愈合并优化 工程组织移植物。在此提案中，我们将使用体外分析和创新的人源化鼠标 测试这些假设的模型，评估CD103+Clahi的发育起源和运输行为 细胞并确定其在皮肤组织修复反应中的功能。