Descrizione del progetto
IRE1 come passaggio tra risposte tollerogeniche e immunogeniche
La funzione di custodia del sistema immunitario, svolta delle cellule dendritiche (DC, Dendritic cells), coordina l’equilibrio tra immunità e tolleranza agli autoantigeni. Il passaggio tra i due stati resta uno degli aspetti più enigmatici in ambito immunologico. L’enzima 1 che richiede l’inositolo (IRE1, Inositol-requiring enzyme) è una proteina del reticolo endoplasmatico (ER, endoplasmic reticulum) e il componente del percorso di risposta alle proteine mal ripiegate per il rilevamento e la risposta allo stress dell’ER. IRE1 contiene un dominio di rilevamento dello stress luminale dell’ER e un dominio delle ribonucleasi citoplasmatiche. L’obiettivo del progetto DCRIDDLE, finanziato dall’UE, è stabilire se IRE1 nelle DC rappresenti il passaggio tra la maturazione tollerogenica e quella immunogenica. Oltre all’impatto esercitato nell’ambito della biologia delle DC, questa ricerca apporterà una nuova comprensione dell’autoimmunità, della malattia del trapianto contro l’ospite e di tutte le condizioni caratterizzate da uno squilibrio tra risposte tollerogeniche e immunogeniche.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
9052 ZWIJNAARDE - GENT
Belgio