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.

摘要 自然杀伤细胞(NK细胞)和先天淋巴样细胞(ILC)I型(ILC1)是宿主抵抗病毒的关键效应物。 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。 尽管它们扮演着重要的角色，但人们对皮肤归巢NK细胞和ILC1的迁移模式知之甚少 器官的选择性或功能，以及它们是否可以选择性地作为靶点。相比之下，器官选择性归巢 针对皮肤和肠道的T细胞亚群被用于疫苗策略和器官特异性疾病的治疗 自身免疫力。这一探索性的建议是基于一个总体假设，即有一个不同的种群 皮肤归巢的NK细胞和ILC1是皮肤宿主防御的关键。研究NK细胞的皮肤转运和 ILC1，我们建议重温绵羊传入淋巴管的经典模型，该模型允许收集 自然杀伤细胞在生理循环过程中通过皮肤。通过对皮肤循环淋巴的靶向分析- 通过NK细胞，我们将评估典型的皮肤归巢受体和效应分子的表达。此外, 我们将使用转录本细胞索引和表位测序(CITE SEQ)来确定基因 皮肤循环NK细胞和ILC1细胞的表达谱及其与对照部位NK细胞的重叠 (肠道淋巴和血液)。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)和皮疹病毒(ECTV)建立小鼠感染模型。我们的 初步研究发现，皮肤循环NK细胞表达高水平的α4β1整合素，其配体 VCAM-1由皮肤血管构造性表达。因此，我们将测试α4β1-整合素在NK中的作用 细胞皮肤归巢与皮肤传播的VACV和ECTV抵抗力的相关性。这也将建立一条管道 以检验皮肤循环NK细胞表达的额外分子在未来研究中的意义。在……里面 综上所述，建议的研究将大大加深我们对皮肤归巢NK细胞和ILC1的了解，以及 我们在皮肤病理中操纵皮肤特异性免疫反应的能力，从感染和 癌症到炎症。