PI3KS IN DCS · The role of the phosphoinositide 3-kinases in the regulation of dendritic cells functions

Phosphoinositide 3-kinases (PI3K) regulate many signalling events, having wide implications for cell biology in many cell types. Among the various catalytic subunit isoforms, p110 is expressed only in some leukocyte cells and was shown to have important potential for the regulation of immune responses. This PI3K isoform was shown to control development of allergic lung disease by affecting Th2 differentiation. Recently, p110 has been proposed to selectively control the production of the pro-allergic cytokine IL-6 in dendritic cells (DC), potentially explaining its importance in Th2 differentiation. We hypothesize in the current project that p110 is a much more central regulator of DC functions which controls most critical functions of these cells, like antigen uptake, processing, migration and T cell stimulatory and polarizing capacity. Also, as PI3Ks are in active balance with phosphatases such as PTEN, we propose that the tandem p110/PTEN, rather than p110 alone, regulates DC function. Therefore, one central theme of the project will be to dissect how p110/PTEN-derived signalling affects the functions of different subsets of DCs that now make up the DC family, as this might provide critical new insights into immunoregulation. For our studies, we will use specific pharmacological antagonists or gene deficient animals, and we will use the latest tools and methods of cellular immunology and molecular biology. A combination of in vivo and in vitro approaches will allow us to depict the implication of p110 in all critical functions of DCs. At the completion of this project, we will have clear insights into how DC function is molecularly controlled by p110 and we will have gained a better understanding of how the p110antagonists that are under clinical development might work to suppress inflammation.