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

doi:10.1016/j.isci.2023.108570

Canonical IRE1 function needed to sustain vigorous natural killer cell proliferation during viral infection

iScience. 2023 Nov 23;26(12):108570. doi: 10.1016/j.isci.2023.108570. eCollection 2023 Dec 15.

Authors

Jessica Vetters^{1

2}, Mary van Helden^{2

3

4}, Clint De Nolf^{1

2

5

6}, Sofie Rennen^{1

2}, Eva Cloots^{1

2}, Evelien Van De Velde^{1

2}, Farzaneh Fayazpour^{1

2}, Justine Van Moorleghem^{2

3}, Manon Vanheerswynghels^{2

3}, Karl Vergote^{2

3}, Louis Boon⁷, Eric Vivier^{8

9

10}, Bart N Lambrecht^{2

3

11}, Sophie Janssens^{1

2}

Affiliations

¹ Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium.
² Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
³ Laboratory for Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium.
⁴ Byondis B.V., Nijmegen, the Netherlands.
⁵ Laboratory for Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium.
⁶ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
⁷ JJP Biologics, Warsaw, Poland.
⁸ Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
⁹ AP-HM, Hôpital de la Timone, Marseille-Immunopôle, Marseille, France.
¹⁰ Innate Pharma Research Laboratories, Innate Pharma, Marseille, France.
¹¹ Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.

Abstract

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.

Keywords: Immunology; Microbiology; Transcriptomics; Virology.