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IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis
  1. Ivan J Fuss1,
  2. Bharat Joshi2,
  3. Zhiqiong Yang1,
  4. Heba Degheidy2,
  5. Stefan Fichtner-Feigl3,
  6. Heitor de Souza4,
  7. Florian Rieder4,
  8. Franco Scaldaferri4,
  9. Anja Schirbel4,
  10. Melania Scarpa4,
  11. Gail West4,
  12. Chuli Yi1,
  13. Lili Xu1,
  14. Pamela Leland2,
  15. Michael Yao1,
  16. Peter Mannon1,
  17. Raj K Puri2,
  18. Claudio Fiocchi4,
  19. Warren Strober1
  1. 1Mucosal Immunity Section, Laboratory of Host Defenses, NIAID NIH, Bethesda, Maryland, USA
  2. 2Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research FDA, Bethesda, Maryland, USA
  3. 3Department of Surgery, University of Regensburg, Regensburg, Germany
  4. 4Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
  1. Correspondence to Dr Ivan J Fuss, Mucosal Immunity Section, LHD, NIH, 10 Center Dr, CRC Building, Room 5W-3864, Bethesda Maryland, USA; ifuss{at}niaid.nih.gov

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 (LPMC) with lyso-sulfatide 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 LPMCs 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; additionally, lyso-sulfatide induces enhanced expression of IL-13Rα2. Finally, blinded phenotypic analysis of UC LP MC using multicolour 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.

Conclusions 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.

  • Inflammatory Bowel Disease
  • Cytokines
  • Ulcerative Colitis
  • Intestinal T Cells

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