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

 描述（由申请人提供）：在本提案中，我们将探索自噬（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。虽然最近的几项研究已经研究了不同的自噬基因在树突状细胞生物学的选定方面的作用，但我们将特别关注Beclin 1。Beclin 1对于早期阶段至关重要， 自噬，但也有几个独特的作用，如最近描述的吞噬作用和内吞膜运输的作用。这些功能对于抗原从细胞外环境中摄取以及分别在MHC II类或MHC I类分子的情况下呈递给CD4 T细胞或CD8 T细胞（交叉呈递）可能是必需的。因此，我们假设Beclin 1缺陷会对树突状细胞活化和抗原交叉呈递产生深远影响，我们已经产生了Beclin 1缺陷小鼠来解决这个问题。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。然后分析Beclin 1缺陷型树突细胞B加工和呈递细胞外抗原（如肿瘤抗原）、分泌不同细胞因子和启动体内T细胞应答的能力。这些研究将极大地提高我们对树突状细胞中激活和抗原加工和呈递过程的理解，从而引发有效的抗肿瘤T细胞免疫应答。

 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.