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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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