Inflammatory rheumatic disorders are common diseases in our society. Not only can they lead to tissue inflammation and damage in joints, often they are also associated with extra-articular manifestations, such as inflammatory bowel disease. Spondyloarthritis is a prototypic form of inflammatory arthritis where such combined gut and joint inflammation may occur. A role for unfolded protein responses (UPR) in the pathophysiology of these diseases has been reported. Our earlier work showed a regulatory role for iNKT cells in experimental spondyloarthritis. Even though iNKT cells are relatively expanded at sites of inflammation, we recently also observed iNKT cell responses to be functionally skewed in patients compared to healthy controls. We therefore sought to investigate potential new mechanisms driving disturbed iNKT cell responses by focusing on ER stress and particularly the type I endoplasmic reticulum (ER) transmembrane protein IRE1-a . We found T cell receptor (TCR)-dependent activation of iNKT cells results in splicing of Xbp-1 mRNA and upregulation of genes associated with induction of the UPR. While tissue distribution and maturation profiles of iNKT cells were unaffected ,  a marked reduction was observed in TCR-dependent cytokine production by iNKT cells in T cell-specific IRE1-a knock-out mice. This impaired cytokine production by IRE1-a -deficient iNKT cells was not due to the altered expression of transcription factors such as T-bet or GATA-3, but rather by reduced mRNA stability for cytokines such as IFNgamma and IL-4. Furthermore, we show that T cell-specific IRE1-a knock-out mice are protected from oxazolone-induced ulcerative colitis. Overall, the data suggest a novel role for ER stress as master regulator of iNKT cell function.