Skin-homing Group-1 innate lymphoid cells in viral defense

病毒防御中的皮肤归巢第 1 组先天淋巴细胞

• 批准号: 10575610
• 负责人: Gudrun Philomena Debes
• 金额: $ 23.4万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575610
• 关键词: Affect; Animal Model; Antitumor Response; Autoimmunity; B-Lymphocytes; Blood; Cannulations; Cell Surface Proteins; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Circulation; Complement; Crohn' s disease; Cutaneous; Distant; Flow Cytometry; Future; Gene Expression; Genetic; Granzyme; Group Homes; Homing; Host Defense; Hypersensitivity; Immune response; Immunity; Immunologic Surveillance; Individual; Infection; Infectious Skin Diseases; Inflammation; Integrin alpha4beta1; Integrins; Intestines; Ligands; Lymph; Lymphocyte; Lymphoid Cell; Malignant Neoplasms; Mesentery; Migration Assay; Modeling; Mouse Pox Virus; Mus; Natural Killer Cells; Organ; Pathology; Pattern; Physiological; Population; Poxviridae; Public Health; Resistance; Rodent; Role; Route; Sheep; Site; Skin; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Tissues; Vaccinia virus; Vascular Cell Adhesion Molecule-1; Viral; Virus; Visit; Work; cell motility; cell type; chemokine receptor; experimental study; improved; inflammatory modulation; migration; mouse model; novel strategies; pathogen; protein expression; receptor; response; sheep model; single cell sequencing; skin disorder; trafficking; transcriptome sequencing; vaccine strategy; vector-borne pathogen

SUMMARY Natural Killer (NK) cells and innate lymphoid cells (ILC) type I (ILC1) are key effectors in host defense against skin-borne viruses and in cutaneous anti-tumor responses; they also modulate inflammatory skin diseases. Despite their critical role, little is known about the migratory patterns of skin-homing NK cells and ILC1, their organ selectivity or functions, and whether they can be selectively targeted. In contrast, organ-selective homing to skin and intestines of T cell subsets is harnessed for vaccine strategies and in the treatment of organ-specific autoimmunity. This exploratory proposal is based on the overall hypothesis that there is a distinct population of skin-homing NK cells and ILC1 that is is key to cutaneous host defense. To study skin-trafficking of NK cells and ILC1, we propose to revisit the classic model of afferent lymph cannulation in the sheep, which allows to collect NK cells during their physiological recirculation through skin. By targeted analysis of skin-recirculating lymph- borne NK cells, we will assess expression of canonical skin-homing receptors and effector molecules. In addition, we will use Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE Seq) to determine gene expression profiles of skin-recirculating NK and ILC1 cells and assess overlap with NK cells in control sites (intestinal lymph and blood). These studies will be complemented by genetic mouse models and viral skin infection mouse models utilizing the poxviruses vaccinia virus (VACV) and ectromelia virus (ECTV). Our preliminary studies discovered that skin-recirculating NK cells express high levels of α4β1-integrin, whose ligand VCAM-1 is constitutively expressed by skin vasculature. Therefore, we will test the role of α4β1-integrin in NK cell skin homing and relevance for resistance to skin-borne VACV and ECTV. This will also establish a pipeline to test the significance of additional molecules expressed by skin-recirculating NK cell in future studies. In summary, the proposed studies will greatly enhance our understanding of skin-homing NK cells and ILC1, and our ability to manipulate skin-specific immune responses in cutaneous pathologies ranging from infection and cancer to inflammation.

总结 自然杀伤（NK）细胞和I型先天性淋巴样细胞（ILC）（ILC 1）是宿主防御肿瘤的关键效应子。 皮肤传播的病毒和皮肤抗肿瘤反应;它们还调节炎性皮肤病。 尽管他们的关键作用，很少有人知道皮肤归巢NK细胞和ILC 1，他们的迁移模式。 器官选择性或功能，以及它们是否可以被选择性靶向。相反，器官选择性归巢 皮肤和肠道的T细胞亚群被用于疫苗策略和治疗器官特异性 自身免疫这一探索性的建议是基于一个总体假设，即有一个独特的人口， 皮肤归巢NK细胞和ILC 1是皮肤宿主防御的关键。研究NK细胞的皮肤运输， ILC 1，我们建议重新审视绵羊传入淋巴管插管的经典模型，该模型允许收集 NK细胞在其通过皮肤的生理再循环期间。通过对皮肤再循环淋巴液的靶向分析， 在NK细胞中，我们将评估典型的皮肤归巢受体和效应分子的表达。此外，本发明还提供了一种方法， 我们将使用通过测序的转录组和表位的细胞索引（CITE Seq）来确定基因 皮肤再循环NK和ILC 1细胞的表达谱，并评估与对照部位NK细胞的重叠 （肠淋巴液和血液）。这些研究将得到遗传小鼠模型和病毒皮肤的补充 利用痘病毒、牛痘病毒（VACV）和鼠痘病毒（ECTV）的感染小鼠模型。我们 初步研究发现，皮肤再循环NK细胞表达高水平的α4β1-整联蛋白，其配体 VCAM-1由皮肤脉管系统组成性表达。因此，我们将测试α4β1-整合素在NK中的作用 细胞皮肤归巢以及与皮肤传播VACV和ECTV抗性的相关性。这也将建立一个管道 以测试皮肤再循环NK细胞表达的其他分子在未来研究中的意义。在 总之，所提出的研究将大大提高我们对皮肤归巢NK细胞和ILC 1的理解， 我们在皮肤病理学中操纵皮肤特异性免疫反应的能力， 从癌症到炎症