The inositol-requiring enzyme 1a (IRE-1a) is a type I endoplasmic reticulum (ER) transmembrane protein containing both kinase and sequence-specific endoribonuclease (RNase) activities. Upon ER stress, activation of IRE-1a results in the cleavage of an 26 base pair intron from mRNA coding for X box binding protein 1 (Xbp-1). Spliced Xbp-1, a potent transcription factor transactivates a number of genes involved in 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 lineage development in T cell-specific IRE-1a knock-out mice revealed comparable tissue distribution and maturation profiles when compared to controls, however, TCR-dependent cytokine production by the NKT1 and NKT17 cell lineage was severely impaired in the absence of IRE-1a. In this context, impaired cytokine production by IRE-1a deficient NKT1 and NKT17 cells was due to reduced mRNA stability for cytokines such as IL-2, IL-4, IL-6, IL-13, TNFa, IFNg and 1L-17A. Furthermore, we show that T cell-specific IRE-1a knock-out mice are protected from oxazolone-induced ulcerative colitis, suggesting that IRE-1a activity within the iNKT cell lineage may be a therapeutic target for treatment of the disease.