权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of autophagy-related protein Vps34 in antigen presentation and self-tolerance

自噬相关蛋白 Vps34 在抗原呈递和自我耐受中的作用

基本信息

批准号：
10224390
负责人：
Luc Van Kaer
金额：
$ 6.95万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224390
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Allergens Animals Antigen Presentation Antigen Presentation Pathway Antigens Apoptotic Autoantigens Autoimmunity Autophagocytosis Biological Assay CD8-Positive T-Lymphocytes Cell Culture Techniques Cell physiology Cells Complement Cross Presentation Defect Dendritic Cells Development Diabetes Mellitus Disease Eating Endocytosis Estrogen receptor positive Exhibits FOXP3 gene Future Generations Genes Genetic Engineering Goals Histocompatibility Antigens Histocompatibility Antigens Class II Human Hypersensitivity Immune Immune response Immune system Immunoglobulins Immunotherapy In Vitro Infectious Agent Islets of Langerhans Life Listeria monocytogenes Lysosomes MHC Class I Genes MHC Class II Genes Malignant Neoplasms Mediating Mediator of activation protein Methods Modeling Molecular Mucins Mus Oral Pathway interactions Peripheral Phagocytosis Pharmacology Phenotype Phosphatidylserines Play Population Process Property Proteins Proteolysis Publishing Quality Control Regulatory T-Lymphocyte Reporter Reporter Genes Role Self Tolerance Signal Transduction T cell response T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymic epithelial cell Thymus Gland Tissues Transgenic Mice Vaccines Vacuolar Protein Sorting Vesicle Work adaptive immune response aged anti-dsDNA antibodies antigen-specific T cells base cell type cytokine human disease improved in vivo neoantigens neoplastic cell novel vaccines organ transplant rejection pathogenic bacteria pathogenic microbe peripheral tolerance prevent receptor response trafficking tumor uptake vaccine development

项目摘要

PROJECT SUMMARY The presentation of self and foreign antigens to T lymphocytes involves a variety of cellular processes, including proteolysis, endocytosis, phagocytosis, vesicle trafficking and autophagy. Our recent studies have investigated the role of autophagy, a self-degradation mechanism, and related cellular processes in MHC class I- and class II-restricted antigen presentation to T lymphocytes, with the long-term goal of manipulating these pathways to prevent or treat human disease. We have focused on a key player in autophagy, the class III phosphatidylinositol- 3 kinase (PI3K) vacuolar protein sorting 34 (Vps34). Our published and unpublished preliminary studies have provided evidence for a key role of Vps34 in both MHC class I- and class II-restricted antigen presentation by dendritic cells (DCs), which are critical players in the induction of tolerance against self-antigens and for initiating adaptive immune responses against foreign antigens. We have shown that the classical MHC class I and class II antigen presentation pathways are enhanced in Vps34-deficient DCs, and that these cells harbor a specific defect in the cross-presentation of apoptotic cell-associated antigens to MHC class I-restricted CD8+ T cells. Moreover, using mice carrying a selective deficiency of Vps34 in their thymic epithelial cells (TECs), we have shown a critical role of Vps34-mediated cellular processes in intrathymic T lymphocyte development. Guided by this scientific premise we propose the overall hypothesis that Vps34-mediated, autophagy-related processes play critical roles in presenting antigens to T lymphocytes and promoting self-tolerance. We will test this hypothesis in the following specific aims: Aim 1 will investigate the contribution of Vps34-mediated functions in unconventional MHC class I- and class II-restricted antigen presentation, and will explore the autophagy-dependent and -independent molecular mechanisms involved. Aim 2 will interrogate the role of Vps34 in the intrathymic development and selection of the T cell repertoire. Aim 3 will explore the role of Vps34 in maintaining peripheral tolerance and controlling T lymphocyte responses against autoantigens. In these studies, we will employ a variety of experimental approaches, including in vitro and in vivo antigen presentation assays, and various genetically engineered animals. As global Vps34 gene-deficiency is incompatible with life, we will employ mice selectively deficient in Vps34 expression in either DCs or TECs. We will complement these studies with cultures of murine and human cells using pharmacological modulators of Vps34 function. We will also take advantage of a variety of reporter animals and transgenic mice expressing neo self-antigens and/or antigen- specific T cell receptors. Collectively, these proposed studies will provide us with a comprehensive mechanistic view of the contribution of the autophagy-related protein Vps34 in antigen presentation, T cell development and selection, peripheral tolerance and T cell immune responsiveness. These proposed studies will be instrumental for the development of improved vaccines and immunotherapies against microbial pathogens and tumors, and for devising methods to induce tolerance against self or foreign antigens.

项目总结