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 generates the transcription factor XBP1s as part of the unfolded
protein response. In addition, its endonuclease domain can also degrade several mRNAs in an ill defined process, termed RIDD.
We found that in one subset of conventional dendritic cells, cDC1s, IRE1 is highly active in steady state, though 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 ability. 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 to tease out the targets of XBP1 and RIDD
separately. Analysis revealed an entirely novel physiological role for RIDD in tolerogenic antigen presentation, closely linked with apoptotic cell uptake.
The aim of the current proposal is to corroborate these data further and uncover the role of the IRE1 branch in DCs. We believe that these findings will have a major impact in the field of DC biology