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.

概括 自然杀伤 (NK) 细胞和 I 型先天淋巴细胞 (ILC) (ILC1) 是宿主防御病毒的关键效应细胞 皮肤传播的病毒和皮肤抗肿瘤反应；它们还调节炎症性皮肤病。 尽管它们发挥着至关重要的作用，但人们对皮肤归巢 NK 细胞和 ILC1 的迁移模式知之甚少。 器官选择性或功能，以及是否可以选择性地靶向器官选择性归巢。 皮肤和肠道的 T 细胞亚群被用于疫苗策略和器官特异性的治疗 这一探索性提议基于这样一个总体假设：存在一个独特的群体。 皮肤归巢 NK 细胞和 ILC1，这是皮肤宿主防御的关键 研究 NK 细胞和皮肤的运输。 ILC1，我们建议重新审视绵羊传入淋巴插管的经典模型，该模型可以收集 NK 细胞在通过皮肤的生理再循环过程中通过对皮肤再循环淋巴液进行针对性分析。 此外，我们将评估典型皮肤归巢受体和效应分子的表达。 我们将通过测序使用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 ILC1 细胞的表达谱，并评估与对照部位 NK 细胞的重叠 （肠道淋巴和血液）将得到遗传小鼠模型和病毒皮肤的补充。 利用痘病毒痘苗病毒（VACV）和节肢动物病毒（ECTV）感染小鼠模型。 初步研究发现皮肤再循环 NK 细胞表达高水平的 α4β1-整合素，其配体 VCAM-1 由皮肤血管系统组成型表达，因此，我们将测试 α4β1-整合素在 NK 中的作用。 细胞皮肤归巢以及对皮肤传播的 VACV 和 ECTV 耐药性的相关性这也将建立一个管道。 测试皮肤再循环 NK 细胞表达的其他分子在未来研究中的重要性。 总之，拟议的研究将极大地增强我们对皮肤归巢 NK 细胞和 ILC1 的理解，并且 我们在皮肤病理学中操纵皮肤特异性免疫反应的能力，包括感染和 癌症到炎症。