Final Report Summary - ORCHESTRATE (Role of plasmacytoid dendritic cells in the orchestration of in vivo immune responses)
The ability of pDCs to migrate from blood to draining lymph organs and to sites of inflammation suggests a central role in the induction of innate immunity as well as in the coordination of adaptive immune functions. It has been shown that pDC-derived IFNs modulate the phenotype and function of conventional DCs. Moreover, pDCs (and cDCs) contribute to the activation of NK cells through both IFN-dependent and independent mechanisms. In addition to type I IFNs, pDCs produce cytokines (TNF) and chemokines (CCL3, CCL4, CXCL10) that selectively attract NK cells and activated T cells. Thus pDC appear specialized for initiation of innate response and have certain capabilities of inducing and modulating adaptive immune responses. But still, there are critical unknowns partly due to not sophisticate enough tools available (e.g. depletion studies performed using mAbs which are not pDC specific).
The research project Role of plasmacytoid dendritic cells in the orchestration of in vivo immune responses was designed to get a better understanding of the fundamental cellular and molecular mechanisms by which pDCs facilitate the establishment of an inflammatory microenvironment, and assist in orchestration of NK cell activity and CD8+ T cell priming by conventional DC (cDC). In this project several new tools and innovative methodologies were used in order to offer new perspectives on pDC biology in vivo. New mouse mutant in which pDCs are the only cell type capable to produce type I IFN allowed us to perform careful analysis of the pDC mediated inflammatory network. The project also benefited from the xMAP luminex technology to characterize the array of cytokines and chemokines produced under various experimental conditions. Results obtained provide the first in vivo model for cell and tissue-restricted type I IFN production and demonstrate that pDC-derived IFNs are sufficient to achieve NK cell mediated control of MCMV infection in restricted organs.