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Deficiency of Invariant NK T Cells in Crohn's Disease and Ulcerative Colitis

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Abstract

The aim of this study was to investigate whether immunoregulatory invariant NK T cells are deficient in Crohn's disease or ulcerative colitis. Blood was collected for flow cytometry from 106 Crohn's disease, 91 ulcerative colitis, and 155 control subjects. Invariant NK T cells were assessed by Vα24 and (α-galactosylceramide/CD1d tetramer markers. Intracellular cytokine was measured after in vitro anti-CD3 antibody stimulation. Vα24+ T cells were quantified in ileocolonic biopsies as mRNA by real-time PCR and by immunofluorescence. Circulating invariant NK T cells were 5.3% of the control levels in Crohn's (P < 0.001) and 7.9% of the control levels in ulcerative colitis (P < 0.001). Interleukin-4 production was impaired in Crohn's disease and ulcerative colitis. Intestinal Vα24 mRNA expression was 7% in Crohn's disease (P < 0.05) and 9% in ulcerative colitis (P < 0.05). Intestinal Vα24+ T cells were 23% in Crohn's disease but not reduced in ulcerative colitis. We conclude that invariant NK T cells are deficient in Crohn's disease and in ulcerative colitis.

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References

  1. Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer Zum Büschenfelde K-H (1995) Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease. Clin Exp Immunol 102:448–455

    Article  PubMed  CAS  Google Scholar 

  2. MacDonald TT (1995) Breakdown of tolerance to the intestinal bacterial flora in inflammatory bowel disease (IBD). Clin Exp Immunol 102:445–447

    Article  PubMed  CAS  Google Scholar 

  3. Kraus TA, Toy L, Chan L, Childs J, Cheifetz A, Mayer L (2004) Failure to induce oral tolerance in Crohn's and ulcerative colitis patients: possible genetic risk. Ann NY Acad Sci 1029:225–238

    Article  PubMed  CAS  Google Scholar 

  4. Kraus TA, Toy L, Chan L, Childs J, Mayer L (2004) Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease. Gastroenterology 126:1771–1778

    Article  PubMed  CAS  Google Scholar 

  5. Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, Fort M, Hershberg RM (2004) Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 113:1296–1306

    Article  PubMed  CAS  Google Scholar 

  6. MacDonald TT, DiSabatino A, Gordon JN (2005) Immunopathogenesis of Crohn's disease. JPEN 29:S118

    CAS  Google Scholar 

  7. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Fiegl S, Yang Z, Exley M, Kitani A, Blumberg RS (2004) Non classical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497

    Article  PubMed  CAS  Google Scholar 

  8. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Burgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129:550–564

    Article  PubMed  CAS  Google Scholar 

  9. Mayer L (2005) Editorial. A novel approach to the treatment of ulcerative colitis. Gastroenterology 128:1117–1119

    Article  PubMed  Google Scholar 

  10. Karttunnen R, Breese EJ, Walker-Smith JA, MacDonald TT (1994) Decreased mucosal interleukin-4 (IL-4) production in gut inflammation. J Clin Pathol 47:1015–1018

    PubMed  CAS  Google Scholar 

  11. West GA, Matsuura T, Levine AD, Klein JS, Fiocchi C (1996) Interleukin 4 in inflammatory bowel disease and mucosal reactivity. Gastroenterology 110:1683–1695

    Article  PubMed  CAS  Google Scholar 

  12. Joyce S, Woods AS, Yewdell JW, Bennink JR, De Silva AD, Boesteanu A, Balk SP, Cotter RJ, Brutkiewicz RR (1998) Natural ligand of mouse CD1d1: cellular glycosylphosphatidylinositol. Science 279:1541–1544

    Article  PubMed  CAS  Google Scholar 

  13. Godfrey DI, Hammond KJL, Poulton LD, Smyth MJ, Baxter AG (2000) NKT cells: facts, functions and fallacies. Immunol Today 21:573–583

    Article  PubMed  CAS  Google Scholar 

  14. Nieda M, Nicol A, Koezuka Y, Kikuchi A, Takahashi T, Nakamura H, Furukawa H, Yabe T, Ishikawa Y, Tadokoro K, Juji T (1999) Activation of human Valpha24NKT cells by alpha-glycosylceramide in a CD1d-restricted and Valpha24TCR-mediated manner. Hum Immunol 60:10–11

    Article  PubMed  CAS  Google Scholar 

  15. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, Koezuka Y, Kronenberg M (2000) Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med 192:741–754

    Article  PubMed  CAS  Google Scholar 

  16. van der Vliet HJ, von Blomberg BM, Nishi N, Reijm M, Voskuyl AE, van Bodegraven AA, Polman CH, Rustemeyer T, Lips P, van den Eertwegh AJ, Giaccone G, Scheper RJ, Pinedo HM (2001) Circulating VSp(alpha24+) Vbeta11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol 100:144–148

    Article  PubMed  CAS  Google Scholar 

  17. Illes Z, Kondo T, Newcombe J, Oka N, Tabira T, Yamamura T (2000) Differential expression of NK T cell Valpha24JalphaQ invariant TCR chain in the lesions of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J Immunol 164:4375–4381

    PubMed  CAS  Google Scholar 

  18. Harper JF (1994) Pertiz’ F test: BASIC programme of a robust multiple comparison test for statistical comparison for statistical analysis of all differences among group means. Comput Biol Med 14:437–445

    Article  Google Scholar 

  19. Maeda T, Kelno H, Asahara H, Taniguchi M, Nishioka K, Sumida T (1999) Decreased TCR AV24αJ18 double-negative T cells in rheumatoid synovium. Rheumatology 38:186–188

    Article  PubMed  CAS  Google Scholar 

  20. Wilson SB, Kemi SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA (1998) Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 391:177–181

    Article  PubMed  CAS  Google Scholar 

  21. Sumida T, Sakamoto A, Murata H, Makino Y, Takahashi H, Yoshida S, Nishioka K, Iwamoto I, Tanguchi M (1995) Selective reduction of T cells bearing invariant V-alpha-24J alpha-Q antigen receptor in patients with systemic sclerosis. J Exp Med 182:1163–1168

    Article  PubMed  CAS  Google Scholar 

  22. Mendiratta SK, Martin WD, Hong S, Boesteanu A, Joyce S, Kaer LV (1997) CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. Immunity 6:469–477

    Article  PubMed  CAS  Google Scholar 

  23. Zhang B, Yamamura T, Kondo T, Fujiwara M, Tabira T (1997) Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J Exp Med 186:1677–1687

    Article  PubMed  CAS  Google Scholar 

  24. Trop S, Samsonov D, Gotsman I, Alper R, Diment J, Ilan Y (1999) Liver-associated lymphocytes expressing NK1.1 are essential for oral immune tolerance induction in a murine model. Hepatology 29:746–755

    Article  PubMed  CAS  Google Scholar 

  25. Saubermann LJ, Beck P, De Jong Y, Pitman RS, Ryan MS, Kim HS, Exley M, Snapper S, Balk SP, Hagen SJ, Kanauchi O, Motoki K, Sakai T, Terhorst C, Koezuka K, Podolsky DK, Blumberg RS (2000) Activation of natural killer T cells by α-galactosylceramide in the presence of CD1d provides protection against colitis in mice. Gastroenterology 119:119–128

    Article  PubMed  CAS  Google Scholar 

  26. Jordan MA, Fletcher J, Baxter AG (2004) Genetic control of NKT cell numbers. Immunol Cell Biol 82:276–284

    Article  PubMed  CAS  Google Scholar 

  27. Berzin SP, Uldrich AP, Pellicci DG, McNab F, Hayakawa Y, Smyth MJ, Godfrey DI (2004) Parallels and distinctions between T and NKT cell development in the thymus. Immunol Cell Biol 82:269–275

    Article  Google Scholar 

  28. Godfrey DI, MacDonald R, Kronenberg M, Smyth MJ, van Kaer L (2004) NKT cells: What's in a name? Nat Rev Immunol 4:231–237

    Article  PubMed  CAS  Google Scholar 

  29. Vainer B, Nelson OH, Hendel J, Horn T, Kirman I (2000) Colonic expression and synthesis of interleukin 13 and interleukin 15 in inflammatory bowel disease. Cytokine 12:1531–1536

    Article  PubMed  CAS  Google Scholar 

  30. Kadivar K, Ruchelli ED, Markwitz JE, Defelice ML, Strogatz ML, Kanzaria MM, Reddy KP, Baldassano RN, von Allmen D, Brown KA (2004) Intestinal interleukin-13 in pediatric inflammatory bowel disease patients. Inflamm Bowel Dis 10:593–598

    Article  PubMed  Google Scholar 

  31. Inoue S, Matsumoto T, Lida M, Mizuno M, Kuroki F, Hoshika K, Shimizu M (1999) Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity. Am J Gastroenterol 94:2441–2446

    Article  PubMed  CAS  Google Scholar 

  32. Yoshimoto T, Paul WE (1994) CD4pos NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med 179:1285–1295

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

R.H.G. was supported by a PhD scholarship from The Queen Elizabeth Hospital Research Foundation. We also gratefully acknowledge funding support for this work from the Broad Medical Research Program. We acknowledge and thank Dr. Mitchell Kronkenberg (La Jolla Institute of Allergy and Immunology, San Diego, California) as the original source of the CD1d transfectants.

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Authors and Affiliations

  1. Basil Hetzel Institute for Medical Research and Department of Medicine, University of Adelaide, Adelaide, and Department of Gastroenterology and Hepatology, DX 465384, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA, 5011, Australia

    Randall H. Grose, Fiona M. Thompson & Adrian G. Cummins

  2. Comparative Genomics Centre, James Cook University, Townsville, Queensland, Australia

    Alan G. Baxter

  3. Department of Pathology and Immunology, Monash University Central and Eastern Clinical School, Victoria, 3181, Australia

    Daniel G. Pellicci

  4. Basil Hetzel Institute for Medical Research and Department of Medicine, University of Adelaide, Adelaide, and Department of Gastroenterology and Hepatology, DX 465384, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA, 5011, Australia

    Adrian G. Cummins

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  1. Randall H. Grose
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  2. Fiona M. Thompson
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  3. Alan G. Baxter
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  5. Adrian G. Cummins
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Correspondence to Adrian G. Cummins.

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Grose, R.H., Thompson, F.M., Baxter, A.G. et al. Deficiency of Invariant NK T Cells in Crohn's Disease and Ulcerative Colitis. Dig Dis Sci 52, 1415–1422 (2007). https://doi.org/10.1007/s10620-006-9261-7

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  • DOI: https://doi.org/10.1007/s10620-006-9261-7

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