Membrane-cytoskeleton crosstalk for the intracellular coordination of immunity

In the human body, dendritic cells (DCs) are part of the immune system's first line of defence. DCs are sentinels of the immune system that patrol the body in search of dangerous invaders. After the capture of pathogens, DCs initiate a complex internal reorganization, named maturation, that triggers DC migration to lymph nodes and the generation of an immune response. DC maturation is characterized by changes in the ability of antigen uptake, processing, presentation and in cell migration. For an effective immune response, DCs need to properly regulate in time and space all these processes. Recent research indicates that the events triggered by antigen recognition are not independent from each other and that their regulation is interconnected. However, how these processes are coordinated is not fully understood. In this project, we identified novel key molecules that regulate the processes of antigen uptake and cell migration in DCs and characterized their function. We found that these molecules have a double role in membrane trafficking and cytoskeleton remodelling by recruiting the molecular motor myosin II. In this way, they modulate the decrease in antigen uptake capability and stimulate cell migration during the process of DC maturation. Altogether the results obtained within this project allowed us a better understanding of the molecules and pathways coordinating DC maturation providing new information not only for a basic understanding of immune cell biology, but also for further applications as to increase the efficacy of DC-based therapeutic cancer vaccines.

The project as generated new knowledge concerning the mechanisms and molecules involved in the process of dendritic cell (DC) maturation. As this is a key process for the generation of a proper immune response, the new findings represent an important advance not only for a basic understanding of immune cell biology, but also for further applications in medicine as to increase the efficacy of DC-based therapeutic cancer vaccines.

In the human body, dendritic cells (DCs) are part of the immune system's first line of defence and orchestrate an immune response. Antigen uptake by DCs triggers a complex maturation program, which involves several cellular changes in the ability of antigen internalization, transport and presentation as well as of migration. For an effective immune response, DCs need to properly regulate in time and space all these processes. However, how these events are coordinated is not fully understood. The aim of this project is to characterize the key players and mechanisms that regulate DC maturation by deploying an innovative multidisciplinary approach that combines molecular and cellular biology, immunology, biochemistry and biophysics. In particular, we will use the following approaches to unravel the contribution of the cytoskeleton/membrane trafficking interplay in DC migration and in antigen uptake, transport, presentation: - bioinformatics to correlate available screening data and find crucial players coordinating DC maturation; - proteomics, to identify the network of interactions involved in this regulation; - state-of the art imaging techniques combined with groundbreaking biophysical assays to perform functional studies of the relevant molecules. Altogether the results obtained within this project will allow us to draw a first model of the molecules and pathways coordinating DC maturation and will provide new information not only for a basic understanding of immune cell biology, but also for further applications as to increase the efficacy of DC-based therapeutic cancer vaccines.