The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity and promotes natural killer cell memory by regulating c-Myc and mitochondrial respiration

Abstract

Abstract Natural killer (NK) cells are critical mediators of host immunity to pathogens. Though historically being considered as a part of the innate immune system, NK cells exhibit adaptive features and can ‘remember’ stimuli like inflammation or viral infection and hence are capable of responding more robustly upon re-encountering the stimulation. Successful design of an NK cell-based therapy would ideally rely on harnessing NK cell memory, the key drivers and regulators of which remain poorly understood. Here, we demonstrate that the endoplasmic reticulum stress sensor IRE1α and its substrate transcription factor XBP1 drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mTOR pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. NK cells with c-Myc haploinsufficency phenocopied IRE1α deficiency, while c-Myc overexpression largely rescued the proliferation defect in IRE1α−/− NK cells. Like c-Myc, IRE1α also promotes oxidative phosphorylation in NK cells. Combined, our study identifies an IRE1α-XBP1-cMyc axis in NK cell immunity; and based on this work, we are currently investigating the role of IRE1 in NK cell memory using novel transgenic mouse models and small molecule drug treatment in primary human cells. We are also evaluating the therapeutic benefit of manipulating IRE1 function in CAR-NK cells to treat cancer. Our ongoing study should advance the current knowledge of NK cell memory and also open new opportunities in cancer therapy for patients with otherwise extremely poor prognoses.