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

 描述(申请人提供)：在这项提案中，我们将探索自噬，一种负责在不同形式的压力下维持细胞内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检验了不同的自噬基因在树突状细胞生物学的特定方面的作用，但我们将专门关注Beclin 1。Beclin 1在早期阶段是必不可少的 自噬，但也有几个独特的作用，如最近描述的作用吞噬和胞内膜运输。这些功能对于从细胞外环境摄取抗原以及在MHC II类或MHC I类分子的背景下分别向CD4T细胞或CD8T细胞递送(交叉递呈)可能是必不可少的。因此，我们假设Beclin 1缺陷将对树突状细胞的激活和抗原交叉提呈产生深远的影响，我们已经培育了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缺陷的树突状细胞在体内处理和呈递细胞外抗原(如肿瘤抗原)、分泌不同的细胞因子和启动T细胞反应的能力。这些研究将极大地提高我们对树突状细胞激活、抗原处理和呈递过程的理解，从而启动有效的抗肿瘤T细胞免疫反应。

 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.