IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis

Abstract

Objective Previous studies have shown that ulcerative colitis (UC) is associated with the presence of lamina propria non-invariant (Type II) NKT cells producing IL-13 and mediating epithelial cell cytotoxicity. Here we sought to define the antigen(s) stimulating the NKT cells and to quantitate these cells in the UC lamina propria. Design Detection of Type II NKT cells in UC lamina propria mononuclear cells (LPMCs) with lysosulfatide loaded tetramer and quantum dot-based flow cytometry and staining. Culture of UC LPMCs with lyso-sulfatide glycolipid to determine sulfatide induction of epithelial cell cytotoxicity, IL-13 production and IL-13Rα2 expression. Blinded quantum dot-based phenotypic analysis to assess UC LPMC expression of IL-13Rα2, CD161 and IL-13. Results Approximately 36% of UC LPMC were lyso-sulfatide tetramer positive whereas few if any control LPMC were positive. When tested, the positive cells were also CD3 and IL-13Rα2 positive. Culture of UC LPMC with lyso-sulfatide glycolipid showed that sulfatide stimulates UC LPMC production of IL-13 and induces UC CD161+ LPMC-mediated cytotoxicity of activated epithelial cells; in addition, lyso-sulfatide induces enhanced expression of IL-13Rα2. Finally, blinded phenotypic analysis of UC LP MC using multi-color quantum dot staining technology showed that approximately 60% of the LPMC bear both IL-13Rα2 and CD161 and most of these cells also produce IL-13. Conclusion These studies show that UC lamina propria is replete with Type II NKT cells responsive to lyso-sulfatide glycolipid and bearing IL-13Rα2. Since lyso-sulfatide is a self-antigen these data suggest that an autoimmune response is involved in UC pathogenesis.

Strategies targeting the IL-4/IL-13 axes in disease

“…They involve the complex interactions of dysbiosis (imbalance of gut microbiome), dysregulated homeostasis of innate and adaptive immune response, diet, and genetic traits [308,309]. Increased IL-13 activity has been implicated in UC based on data from some mouse models and human intestinal epithelial cell ex vivo studies [310][311][312][313][314]. In an oxazolone-induced colitis model in mice which mimics key aspects of UC in humans, a marked IL-13 response from CD4 + NKT cells (not conventional CD4 + T cells) was observed [310].…”

Contentious host–microbiota relationship in inflammatory bowel disease – can foes become friends again?

“…Recently, the expression of CXCL16, a bacterial scavenger receptor, was found to be increased in the colonic epithelium of UC patients with both active disease and in remission [89], suggesting an impaired host-microbe crosstalk in the non-active disease. The impaired host-microbe crosstalk in the epithelial lining is suggested to be one of the first steps in the pathogenesis of IBD leading to natural killer T-cellmediated epithelial cell cytotoxicity and autoimmunelike responses [90].…”

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

“…Sulfatide also stimulated phosphorylation of transcription factor Sp1 in hepatocellular carcinoma cells through Erk1/2 signaling, which in turn increased expression of the integrin αV subunit, another protein involved in metastasis (42). In ulcerative colitis, the mucosa is enriched with type II NKT cells, and sulfatide binds to these cells to induce production of IL-13, which mediates epithelial cell cytotoxicity (43). In asthma, transgenic mice overexpressing the human GSDMB developed asthmatic symptoms, and an overexpression of GSDMB in bronchial epithelial cells induced the expression of 5-lipoxygenase, which in turn induced TGF-β1 expression (44).…”