Grant: Project Grant

Genetic variations and environmental factors influence host immune responses and can lead to susceptibility to pathogens and to inflammatory diseases. Two regulators of gene expression in immune cells, the transcription factors IRF1 and IRF8, have been implicated in life-threatening immunodeficiencies and with chronic inflammatory diseases. We and others have shown that both factors are essential in the development of acute neuroinflammation caused by malaria and for the defense against intracellular pathogens; highlighting their major implication in Th1 immunity. We have recently dissected the critical role of IRF1 and IRF8 in the epigenetic control of innate immune cells and revealed that their target genes are also associated with acute and chronic inflammatory conditions. In this work, we propose to investigate the intrinsic role of IRF1 and IRF8 in cells of the adaptive immune compartment (T lymphocytes) to better understand their involvement in human pathologies. Moreover, building on the IRF1 and IRF8 transcriptional networks that we have defined, we developed a bioinformatic prioritization method to identify genes that could be involved in chronic inflammatory diseases, such as inflammatory bowel disease and multiple sclerosis. Amongst the strong candidates, some poorly studied transcriptional regulators were selected for functional validation. These will be investigated using genetically engineered animal and cell models, with a combination of functional genomics and immunological characterization methods. The project will further our understanding of the functional role of these important transcriptional regulators in inflammation and ascertain their role in immune cell biology; shedding light on the possible mechanisms behind their genetic association to chronic inflammatory diseases. A deep understanding of the genetic components and its translation into innovative therapeutic strategies is key to fight inflammatory diseases.