Integrating Cell Death and DC activation: utilizing "clean" cell death systems to characterize the relationship between cell stress and immunity – ANUBIS

This project addresses the relationship between cell death and immune activation. Our proposal is a fundamental research project that will impact on our understanding of immune activation, T cell priming and host-pathogen interactions. We will focus on the role of dying cells as triggers of immune activation and dendritic cell cross-priming. Indeed, cell death has been implicated in host defense, counteracting viral infection by modulating cellular pathways and triggering pro-inflammatory pathways (e.g. production of type I interferons); and limiting malignant transformed. Moreover, induction of cell death is a principle strategy for the treatment of cancer; and there is greater attention as to how chemotherapy may be tailored to maximize the engagement of the immune system for additional clinical impact. The field of cell death has advanced over the last 15yrs and we have moved from having two forms of cell death in the early 1990s (necrosis and apoptosis), to now having at least five well defined forms of programmed cell death (intrinsic apoptosis, extrinsic apoptosis, pyroptosis, autophagic cell death, and necroptosis). Remarkably, the mechanisms of cell death influences the activation state of phagocytes that are responsible for their clearance. It is in this context that we propose to define the outcome of dendritic cells engulfing dead cells, with a focus on the impact on the dendritic cell activation state, their production of inflammatory cytokines / chemokines, and the cross-presentation of antigen. As such, our project will integrate the spatial and temporal mechanisms involved in the host response to activation of pathogen recognition receptors (PRR) or infection – from dying cell – to phagocyte – to the stimulation of antigen specific T cells. This will include our defining the molecular and cellular aspects of the different death pathway(s) in the stimulation of DCs and subsequent activation of an innate immune and adaptive immune response.

Cell death is a central mechanism to all living processes – it is implicated in host response to infection, and plays a critical role in tumorigenesis and autoimmune diseases. Dendritic cells are considered central to the orchestration of inflammatory responses and they serve as a critical bridge between the innate and adaptive arms of the immune response. As such, our efforts are positioned to have a broad impact on the mechanistic understanding of immune regulation. Moreover, we recognize that the cell death pathway(s) may serve as a target for novel therapeutic agents and the proposed work will help identify novel strategies for modulating inflammatory diseases.

The partnership between the Albert and Amigorena laboratories will capitalize on unique expertise and a shared interest in the fundamental mechanisms of phagocytosis and cross-presentation.