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.
This proposal focuses on the role of autophagic protein Beclin 1 in dendritic cell development, activation and antigen presentation of tumor antigens responsible for eliciting anti-tumor T cell responses. We hypothesize Beclin 1 might have a significant impact on dendritic cell activation and presentation of tumor antigens to T cells. Beclin 1 deficient mice required to accomplish this task have already been generated and initial characterization of dendritic cell completed. The project should provide answers to several important questions concerning the essential role of dendritic cell in the activation of adaptive immunity against tumors and might provide new clues for anti-tumor immune therapy. As such, it could possibly have a significant impact on public health in general.
|Arsov, Ivica; Adebayo, Adeola; Kucerova-Levisohn, Martina et al. (2011) A role for autophagic protein beclin 1 early in lymphocyte development. J Immunol 186:2201-9|