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

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Vetters, Jessica | van Helden, Mary | de Nolf, Clint | Rennen, Sofie | Cloots, Eva | van de Velde, Evelien | Fayazpour, Farzaneh | van Moorleghem, Justine | Vanheerswynghels, Manon | Vergote, Karl | Boon, Louis | Vivier, Eric | Lambrecht, Bart, N | Janssens, Sophie

Edité par CCSD ; Elsevier -

International audience. 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.

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