The impact of autophagy on antigen cross-presentation in dendritic cells

自噬对树突状细胞抗原交叉呈递的影响

基本信息

批准号：
9451934
负责人：
IVICA ARSOV
金额：
$ 12.9万
依托单位：
YORK COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9451934
关键词：
Address Animals Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Autophagocytosis CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cellular biology Cross Presentation Data Dendritic Cells Dendritic cell activation Development Digestion Endocytosis Environment Event Generations Genes Histocompatibility Antigens Class I Homeostasis ITGAX gene Immune Immune response Inflammatory LoxP-flanked allele MHC Class II Genes Mediating Membrane Mus Ovalbumin Pathway interactions Peptide/MHC Complex Phagocytosis Play Process Production Progress Reports Proteins Public Health Reporting Role Stimulus Stress T cell response T-Cell Activation T-Lymphocyte Testing Toll-like receptors Transgenic Mice Tumor Antigens Tumor-Derived adaptive immunity aluminum sulfate cytokine extracellular improved in vivo insight neoplasm immunotherapy novel pathogen public health relevance trafficking tumor uptake

项目摘要

DESCRIPTION (provided by applicant): In this proposal we will explore the impact of autophagy, a self-digestion mechanism responsible for maintaining cellular homeostasis under different forms of stress, on dendritic cell development and function. While several recent studies have examined the role of different autophagic genes on selected aspects of dendritic cell biology, we will specifically focus on Beclin 1. Beclin 1 is essential for the early stages of autophagy, but also has several unique roles, such as the recently described roles in phagocytosis and endocytic membrane trafficking. These functions could be essential for antigen uptake from the extracellular environment and presentation to either CD4 T cells or CD8 T cells (cross-presentation) in the context of MHC class II or MHC class I molecules, respectively. We therefore hypothesize that Beclin 1 deficiency would have a profound impact on dendritic cell activation and antigen cross-presentation and we have already generated Beclin 1-deficient mice to address this question. We will first examine if normal development and activation of dendritic cells requires Beclin 1. Beclin 1-deficient dendritic cells will then b analyzed for their ability to process and present extracellular antigens, such as tumor antigens, secrete different cytokines and initiate T cell responses in vivo. These studies should greatly improve our understanding of the processes of activation and antigen processing and presentation in dendritic cells leading to initiation of an effective anti-tumor T cell immune response.

描述（由申请人提供）：在本提案中，我们将探讨自噬（一种负责在不同形式的应激下维持细胞稳态的自我消化机制）对树突状细胞发育和功能的影响，而最近的几项研究已经检验了自噬的作用。不同的自噬基因对树突状细胞生物学的选定方面的影响，我们将特别关注 Beclin 1。Beclin 1 对于树突状细胞生物学的早期阶段至关重要自噬，但也有一些独特的作用，例如最近描述的吞噬作用和内吞膜运输中的作用，这些功能对于从细胞外环境摄取抗原并呈递给 CD4 T 细胞或 CD8 T 细胞（交叉呈递）至关重要。因此，我们分别在 MHC II 类或 MHC I 类分子的背景下发现 Beclin 1 缺陷将对树突状细胞激活和抗原交叉呈递产生深远影响，并且我们已经生成了 Beclin。为了解决这个问题，我们将首先检查树突状细胞的正常发育和激活是否需要 Beclin 1。然后将分析 Beclin 1 缺陷的树突状细胞处理和呈递细胞外抗原（例如肿瘤抗原）的能力。分泌不同的细胞因子并启动体内 T 细胞反应，这些研究将极大地提高我们对树突状细胞的激活、抗原加工和呈递过程的理解，从而启动有效的抗肿瘤 T 细胞免疫。回复。