Sophie Janssens - DC-RIDDLE

Description of the PI

Sophie Janssens was born in Schoten in 1973. She received her Master in Biology at the University of Antwerp and her PhD in Sciences at the University of Ghent (2003), where she studied the role of MyD88 in innate immune signalling. She went for her postdoc to the lab of Prof. J. Tschopp at the University of Lausanne (2005) to work on the PIDDosome, a complex involved in cell fate decisions upon DNA damage. After a second postdoc in a Peripheral Neuropathy Group at the University of Antwerp, she became Full Professor at the University of Ghent to coordinate a novel research line on ER stress and inflammation (2011).

Her research team focuses on the role of the unfolded protein response in immune cells. They discovered that amongst all immune cells in our body, one subset of conventional dendritic cells (DC), the cDC1s, shows a particular high activation of the IRE1/XBP1 branch in steady state. This does not lead to the activation of a canonical XBP1 gene signature, but appears linked to their specific function in dead cell-derived antigen presentation. The Janssens lab is currently unraveling how the IRE1alpha branch in DCs shapes their immune responses, both in steady state as well as during viral infections.

Description of the project

Dendritic cells (DCs) play a crucial role as gatekeepers of the immune system, coordinating the balance between protective immunity and tolerance to self-antigens. What determines the switch between immunogenic versus tolerogenic antigen presentation remains one of the most puzzling questions in immunology. My team recently discovered an unanticipated link between a conserved stress response in the endoplasmic reticulum (ER) and tolerogenic DC maturation, thereby setting the stage for new insights in this fundamental branch in immunology.

Specifically, we found that one of the branches of the unfolded protein response (UPR), the IRE1/XBP1 signaling axis, is constitutively active in murine dendritic cells (cDC1s), without any signs of an overt UPR gene signature. Based on preliminary data we hypothesize that IRE1 is activated by apoptotic cell uptake, orchestrating a metabolic response from the ER. This entirely novel physiological function for IRE1 entails a paradigm shift in the UPR field, as it reveals that IRE1’s functions might stretch far from its well-established function induced by chronic ER stress. The aim of my research program is to understand by which signals IRE1 is activated in DCs and how it might affect the switch between tolerogenic and immunogenic maturation. To this end, we will dissect its function in vivo both in steady-state conditions and in conditions of danger (viral infection models). I envisage that my research program will not only have a large impact on the field of DC biology and apoptotic cell clearance, but might also yield new insights in diseases like autoimmunity, graft versus host disease or tumor immunology, all associated with disturbed balances between tolerogenic and immunogenic responses.

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