Crucial role for XBP1 in several aspects of DC functioning and homeostasis

4 May 2017
Type 1 conventional dendritic cells (cDC1s) play a crucial role in orchestrating the balance between protective anti-viral or anti-tumour immunity and tolerance to self-antigens. What determines this balance remains poorly understood, but over the past few years several signaling pathways have been unraveled that help DCs to perform their specialized crosspresentation function. VIB-UGent researchers Sophie Janssens and Bart Lambrecht previously found that loss of XBP1, a major transcription factor in the unfolded protein response, in cDC1s cripples their ability to crosspresent dead-cell derived antigens. This is due to the overactivation of IRE1 in XBP1-deficient DCs and induction of regulated IRE1 dependent mRNA decay (RIDD), which leads to the degradation of key target molecules within the crosspresentation pathway (Osorio et al., Nat Imm, 2014).

In this new work from Simon Tavernier and colleagues from the groups of Janssens and Lambrecht, an additonal role for XBP1 in maintaining the survival of cDC1s in mucosal tissues was discovered. 

Prof. Sophie Janssens (VIB-UGent): “We uncovered a role for XBP1 in the survival of lung but not intestinal or splenic cDC1s, showing a tissue specific role for the IRE1/XBP1 branch in maintaining DC homeostasis. By exploring the mechanisms underlying this tissue specific response we found that lung and intestinal DCs mount different adaptive responses in the face of chronic ER stress, which is mimicked in our mouse model by the loss of XBP1.”

Dr. Simon Tavernier (VIB-UGent): “Intestinal cDC1s show a highly increased IRE1 endonuclease activity compared to lung cDC1s. In the field of ER stress, the physiological role of RIDD is still highly debated, but we clearly establish that in dendritic cells RIDD plays a protective role and helps the cells to survive the loss of XBP1.”

Prof. Sophie Janssens (VIB-UGent): “How RIDD mediates this protective activity is still elusive and none of the currently known RIDD targets appeared to be involved in determining the switch between life and death in DCs. We identified novel downstream RIDD targets in lipid metabolic pathways and are currently further exploring how altered lipid metabolism, DC function and DCs survival are linked.”

Prof. Bart Lambrecht (VIB-UGent): “ Still, while we don’t have the complete picture yet, our study uncovers that adaptive responses are differentially hardwired in DCs across different tissues and that the IRE1/XBP1 pathway appears to play a crucial role in several aspects of DC functioning and homeostasis. In light of the established role of DCs in cancer immunotherapy, we believe that understanding these stress signaling networks will be crucial to develop the next generation DC therapy.”

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival, Tavernier et al., Nature Cell Biology 2017

Simon Tavernier, Sofie Janssens, Bart Lambrecht