Modulation of the unfolded protein response via XBP1 splicing: a novel mechanism that regulates Natural Killer cell effector function. (172.10)

Abstract The transcriptional factor X-box-binding protein 1 (XBP1), a critical gene in the unfolded protein response (UPR), has recently been demonstrated to be essential for the development, survival and function of B cells, T cells and Dendritic Cells. However, the involvement of the UPR in Natural Killer (NK) cell function has yet to be investigated. To address this we examined XBP1 during NK cell killing. Following activation of the UPR, XBP1 mRNA is converted to its active form (XBP1s) through splicing mediated by inositol-requiring enzyme-1 (IRE1). Splicing of XBP1 mRNA was observed within 1 hour following initiation of NK cell direct-cytotoxicity or antibody-dependent cell-mediated cytotoxicity (ADCC) towards leukaemia or lymphoma target cells. This indicates that the IRE1/XBP1 arm of the UPR is rapidly induced during killing of target cells. To determine the impact of induction of the IRE1/XBP1 pathway on NK cell cytotoxicity, IRE1 mediated splicing of XBP1 was pharmacologically inhibited. This significantly impaired both NK cell mediated direct-cytotoxicity and ADCC. Together these results indicate that induction of the UPR and splicing of XBP1s is essential for optimal NK cell cytotoxicity and demonstrates a novel mechanism to modulate NK cell effector function.