Dendritic cells (DCs) play a crucial role as gatekeepers of the immune system, orchestrating the balance between protective immunity and tolerance to self antigens. What determines this switch between tolerogenic vs immunogenic antigen presentation remains poorly understood. IRE1 is an endonuclease that splices XBP1 mRNA to form the transcription factor XBP1s as part of the unfolded protein response (UPR). In addition, the IRE1 endonuclease domain can also degrade several mRNAs in an ill defined process, termed Regulated IRE1 dependent mRNA decay (RIDD). My host lab uncovered that one subset of conventional dendritic cells, cDC1s, uniquely shows high activation of IRE1 in steady state. This was not reflected by the presence of a typical XBP1 gene signature. cDC1s are specialized in crosspresentation of dead cell-derived antigens and loss of XBP1 crippled this. This defect was due to the aberrant hyperactivation of IRE1 and RIDD in XBP1 DCs, rather than to the loss of XBP1s itself. To probe the role of XBP1, a transcriptome analysis was done on splenic cDC1s sorted from WT, XBP1KO or XBP1/IRE1KO mice. This allows to tease out the targets of XBP1 and RIDD separately. Analysis revealed an entirely novel physiological role for RIDD in tolerogenic antigen presentation. Moreover, the pathway is closely
linked with apoptotic cell uptake. The aim of my proposal is to explore and corroborate these findings to nail down the function of the IRE1/XBP1 branch in DCs in steady state.