Canonical IRE1 function needed to sustain vigorous natural killer cell proliferation during viral infection
Jessica Vetters,
Mary van Helden,
Clint De Nolf,
Sofie Rennen,
Eva Cloots,
Evelien Van De Velde,
Farzaneh Fayazpour,
Justine Van Moorleghem,
Manon Vanheerswynghels,
Karl Vergote,
Louis Boon,
Eric Vivier,
Bart N. Lambrecht,
Sophie Janssens
Affiliations
Jessica Vetters
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
Mary van Helden
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium; Byondis B.V., Nijmegen, the Netherlands
Clint De Nolf
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
Sofie Rennen
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
Eva Cloots
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
Evelien Van De Velde
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
Farzaneh Fayazpour
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
Justine Van Moorleghem
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
Manon Vanheerswynghels
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
Karl Vergote
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
Louis Boon
JJP Biologics, Warsaw, Poland
Eric Vivier
Aix Marseille University, CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Marseille, France; AP-HM, Hôpital de la Timone, Marseille-Immunopôle, Marseille, France; Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
Bart N. Lambrecht
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium; Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands
Sophie Janssens
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Corresponding author
Summary: The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency of IRE1 and its downstream transcription factor XBP1 in NKp46+ NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1-sufficient Ly49H+ NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that IRE1/XBP1 activation is required during vigorous NK cell proliferation early upon viral infection, as part of a canonical UPR response.
