Previous studies of a murine model of ulcerative colitis (UC), oxazolone-colitis, as well as human UC have provided evidence that these forms of intestinal inflammation are marked by the presence of lamina propria CD4 T cells that by several criteria are Type II (non-invariant) NKT cells. Moreover, these studies showed that upon stimulation, these NKT cells produce IL-13 and exhibit cytotoxicity for epithelial cells that is augmented by IL-13. While these previous studies suggested that NKT cells play an important pathogenic role in UC, they did notaddress two important questions. First, they did not define a glycolipid antigen responsible for TCR stimulation of the NKT cells, and for thus initiating or maintaining the UC inflammatory process. Second, they did not identify an NKT cell surface marker that could be used to quantitatively assess or functionally evaluate these NKT cells in the lamina propria of patients with UC. In the present studies we address these unanswered questions.We establish first using CD1d-tetramer binding studies that the lamina propria of UC patients contains a substantial population of CD3 T cells whose TCR binds lyso-sulfatide glycolipid, an endogenous glycolipid antigen previously shown to stimulate Type II NKT cells. Further evidence that UC NKT cells have TCRs responsive to sulfatide glycolipid came from studies showing that this antigen stimulates UC lamina propria cells to secrete IL-13, and to exhibit enhanced epithelial cell cytotoxicity. Additionally, we show that sulfatide glycolipid antigen upregulates NKT cell expression of IL-13Rα2, a high-affinity IL-13 receptor. Finally, we performed extensive studies of the phenotype of IL-13Rα2-expressing cells, and using this receptor as a UC NKT cell marker obtained evidence that NKT cells make up the majority of cells in the UC lamina propria. The significance of these studies is severalfold. First, since sulfitide are derived from endogenous cells, these studies strongly suggest that the pathologic process in ulcerative colitis can be considered a form of autoimmunity, albeit one that depends on an underlying defect in epithelial cell reactivity to the gut microbiome. Second, these studies support the view that either sulfitide tetramer-positive cells or IL-13Ralpha2-positive cells can be used as a diagnostic marker in UC.
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