Cytokine production by the invariant natural killer T cell lineage is regulated by the transmembrane protein kinase IRE1α — ASN Events
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Cytokine production by the invariant natural killer T cell lineage is regulated by the transmembrane protein kinase IRE1α (#102)

Srinath Govindarajan 1 2 , Eveline Verheugen 1 2 , Takao Iwawaki 3 , Dirk Elewaut 1 2 , Michael B Drennan 1 2
  1. Lab of Molecular Immunology and Inflammation, Rheumatology, Ghent University Hospital, Ghent, Belgium
  2. VIB Inflammation research Center, Ghent University, Gent, Belgium
  3. Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma , Japan

The inositol-requiring enzyme 1a (IRE1a) is a type I endoplasmic reticulum (ER) transmembrane protein containing both kinase and sequence-specific endoribonuclease (RNase) activities. Upon ER stress, activation of IRE1a results in the cleavage of an intron from mRNA coding for X box binding protein 1 (Xbp-1), thereby generating a transcription factor that regulates the expression of genes important for restoring cellular homeostasis. In this study, we show that T cell receptor (TCR)-dependent activation of the invariant natural killer T (iNKT) cell lineage results in splicing of Xbp-1 mRNA as well as the upregulation of genes associated with induction of the unfolded protein response (UPR). A subsequent analysis of iNKT cell development in T cell-specific IRE1a knock-out mice revealed comparable tissue distribution and maturation profiles when compared to controls, however, TCR-dependent cytokine production by the iNKT cell lineage was severely impaired in the absence of IRE1a. In this context, impaired cytokine production by IRE1a-deficient iNKT cells was not due to the altered expression of transcription factors such as T-bet or GATA-3, but was consequence reduced mRNA stability for cytokines such as IFNg and IL-4. Furthermore, we show that T cell-specific IRE1a knock-out mice are protected from oxazolone-induced ulcerative colitis, suggesting that IRE1a activity within the iNKT cell lineage may be a therapeutic target for treatment of the disease.