The IRE1 pathway of the UPR regulates cDC1 function during acute T. gondii infection

Induction of the unfolded protein response (UPR) has emerged as a key regulatory mechanism that controls inflammatory processes, notably in response to infections. We previously demonstrated that induction of the UPR sensor IRE1 in Bone-Marrow derived Dendritic Cells (BMDCs) infected by Toxoplasma gondii promotes inflammatory cytokine production and MHC-I presentation of secreted parasite antigens. In addition, in vivo, specific deletion of IRE1 in DCs correlated with impaired cDC1 expansion and altered T cell mediated protective responses resulting in uncontrolled parasite dissemination and high susceptibility to infection.
In the current study, we explored these findings further and aimed to dissect how loss of IRE1 affects DC function in response to T. gondii infection. We showed that IRE1 is specifically needed at an early step in the DC maturation process, at the moment that DCs are maximally engulfing antigens, associated with increased lipid influx. IRE1 appears to regulate key signalling pathways involved in lipid homeostasis but also in the induction of type I interferon response, known to be involved in cDC1 maturation and immunogenic functions.
Targeting the UPR may open new strategies to boost antigen presentation by cDC during an infection and ameliorate vaccine efficacy.