Stabilization of cytokine mRNAs in iNKT cells requires the serine-threonine\xa0kinase IRE1alpha

Srinath Govindarajan,Yehudi Bloch,Simon Tavernier,Renée Van Der Cruyssen,Michael B Drennan,Sophie Janssens,Eveline Verheugen,Dirk Elewaut,Djoere Gaublomme,Sofie Van Gassen,Takao Iwawaki,Savvas N Savvides,Bart N Lambrecht,Yvan Saeys

doi:10.1038/s41467-018-07758-x

Abstract

Activated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. Here we show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), links key cellular processes required for iNKT cell effector functions in specific iNKT subsets, in which TCR-dependent activation of IRE1α is associated with downstream activation of p38 MAPK and the stabilization of preformed cytokine mRNAs. Importantly, genetic deletion of IRE1α in iNKT cells reduces cytokine production and protects mice from oxazolone colitis. We therefore propose that an IRE1α-dependent signaling cascade couples constitutive cytokine mRNA expression to the rapid induction of cytokine secretion and effector functions in activated iNKT cells.

Highlights

Activated invariant natural killer T cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear
We propose that inositol-requiring enzyme 1α (IRE1α), a unfolded protein response (UPR) sensor, links key cellular processes involved in the regulation of cytokine production by activated iNKT cells
Results presented here show that T-cell receptor (TCR)-mediated stimulation of the NKT1 and NKT17 sublineages results in autophosphorylation of IRE1α and subsequent splicing of XBP1, a UPR-specific transcription factor, that is involved in remodeling of the endoplasmic reticulum (ER) and preparing cells for enhanced cytokine secretion

Summary

Introduction

Activated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. A hallmark feature of iNKT cells is their ability to rapidly produce and secrete immunomodulatory cytokines following T-cell receptor (TCR) ligation, implicating them in a range of inflammatory, allergic, and autoimmune diseases[1]. This functional aspect of iNKT cell biology is not fully understood, it has been suggested that the presence of preformed cytokine mRNAs as well as histone acetylation of distinct cytokine loci facilitate rapid iNKT cell cytokine production[2,3].

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