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A novel physiological role for IRE1 and RIDD..., maintaining the balance between tolerance and immunity?

Project description

IRE1 as a switch between tolerogenic and immunogenic responses

Dendritic cells (DCs) function as gatekeepers of the immune system, coordinating the balance between immunity and tolerance to self-antigens. The switch between the two states remains one of the most puzzling questions in immunology. Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER) protein and the component of the unfolded protein response pathway for sensing and responding to ER stress. IRE1 contains an ER luminal stress-sensing domain and a cytoplasmic RNase domain. The aim of the EU-funded DCRIDDLE project is to determine if IRE1 in DCs is the switch between tolerogenic and immunogenic maturation. Apart from its impact on the field of DC biology, this research will bring a new understanding of autoimmunity, graft versus host disease and all conditions characterised by an imbalance between tolerogenic and immunogenic responses.

Objective

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 to ensure tolerogenic antigen presentation. 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 establish whether IRE1 in DCs is the hitherto illusive 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). In line with our data, IRE1 has recently been identified as a candidate gene for autoimmune disease based on Genome Wide Association Studies (GWAS). Therefore, I envisage that my research program will not only have a large impact on the field of DC biology and apoptotic cell clearance, but will 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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Coordinator

VIB VZW
Net EU contribution
€ 1 999 196,00
Address
Rijvisschestraat 120
9052 Zwijnaarde - gent
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
Links
Other funding
€ 0,00

Beneficiaries (1)