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The effect of oral tolerance on the roles of small intestinal intraepithelial lymphocytes in murine colitis induced by dextran sodium sulfate

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Backgrounds and aims

There is increasing evidence that gut-derived intraepithelial lymphocytes have potent cytolytic and immunoregulatory functions, which they use to sustain epithelial integrity. The aims of this study were to investigate the roles of small intestinal intraepithelial lymphocytes (SI-IELs) in oral tolerance and dextran sodium sulfate (DSS)-induced colitis.

Methods

SI-IELs or sorted γδ T cells from untreated, colitis, and colitis-extracted protein (CEP)-fed colitis mice were adoptively transferred to BALB/c mice; colitis was then induced with DSS. Cytokines were analyzed in sera from mice and culture supernatants.

Results

Transfer of SI-IELs or sorted γδ T cells from untreated and colitis mice all alleviated experimental colitis. Mice orally administered with five low doses of CEP showed less severe symptoms and histological injury. SI-IELs from CEP-fed colitis mice more significantly ameliorated colitis than those from control mice (weight, 94.1 ± 2.5% vs. 89.8 ± 2.6%, p < 0.05; disease activity index, 7.2 ± 1.2 vs. 8.7 ± 1.9, p < 0.05; histological scores, 22.1 ± 2.8 vs. 25.7 ± 2.1, p < 0.05, n = 8 per group); however, not did SI-γδ IELs from CEP-fed colitis mice. Alleviation of colitis was accompanied by an increase of TGF-β1 secretion and no change of IFN-γ in sera and culture supernatants. The level of serum TGF-β1 was negatively related to the severity of colitis.

Conclusions

The protective effects of SI-IELs in DSS-induced colitis were partly accomplished by γδ T cells and could be mediated by TGF-β but were not associated with IFN-γ. Oral tolerance strengthens the suppressive effects of regulatory subsets in SI-IELs.

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References

  1. Kunisawa J, Takahashi I, Kiyono H (2007) Intraepithelial lymphocytes: their shared and divergent immunological behaviors in the small and large intestine. Immunol Rev 215:136–153

    Article  PubMed  CAS  Google Scholar 

  2. Cheroutre H (2005) IELs: enforcing law and order in the court of the intestinal epithelium. Immunol Rev 206:114–131

    Article  PubMed  Google Scholar 

  3. Buzoni-Gatel D, Lepage AC, Mier-Poisson IH, Bout DT, Kasper LH (1997) Adoptive transfer of gut intraepithelial lymphocytes protects against murine infection with Toxoplasma gondii. J Immunol 158:5883–5889

    PubMed  CAS  Google Scholar 

  4. Muller S, Buhler-Jungo M, Mueller C (2000) Intestinal intraepithelial lymphocytes exert potent protective cytotoxic activity during an acute virus infection. J Immunol 164:1986–1994

    PubMed  CAS  Google Scholar 

  5. Nanno M, Shiohara T, Yamamoto H, Kawakami K, Ishikawa H (2007) gammadelta T cells: firefighters or fire boosters in the front lines of inflammatory responses. Immunol Rev 215:103–113

    Article  PubMed  CAS  Google Scholar 

  6. Komano H, Fujiura Y, Kawaguchi M, Matsumoto S, Hashimoto Y, Obana S, Mombaerts P, Tonegawa S, Yamamoto H, Itohara S (1995) Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 92:6147–6151

    Article  PubMed  CAS  Google Scholar 

  7. Dalton JE, Cruickshank SM, Egan CE, Mears R, Newton DJ, Andrew EM, Lawrence B, Howell G, Else KJ, Gubbels MJ, Striepen B, Smith JE, White SJ, Carding SR (2006) Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 131:818–829

    Article  PubMed  CAS  Google Scholar 

  8. Yang H, Antony PA, Wildhaber BE, Teitelbaum DH (2004) Intestinal intraepithelial lymphocyte gamma delta-T cell-derived keratinocyte growth factor modulates epithelial growth in the mouse. J Immunol 172:4151–4158

    PubMed  CAS  Google Scholar 

  9. Mengel J, Cardillo F, Aroeira LS, Williams O, Russo M, Vaz NM (1995) Anti-gamma delta T cell antibody blocks the induction and maintenance of oral tolerance to ovalbumin in mice. Immunol Lett 48:97–102

    Article  PubMed  CAS  Google Scholar 

  10. Fujihashi K, Dohi T, Kweon MN, McGhee JR, Koga T, Cooper MD, Tonegawa S, Kiyono H (1999) gammadelta T cells regulate mucosally induced tolerance in a dose-dependent fashion. Int Immunol 11:1907–1916

    Article  PubMed  CAS  Google Scholar 

  11. Ke Y, Pearce K, Lake JP, Ziegler HK, Kapp JA (1997) Gamma delta T lymphocytes regulate the induction and maintenance of oral tolerance. J Immunol 158:3610–3618

    PubMed  CAS  Google Scholar 

  12. Locke NR, Stankovic S, Funda DP, Harrison LC (2006) TCR gamma delta intraepithelial lymphocytes are required for self-tolerance. J Immunol 176:6553–6559

    PubMed  CAS  Google Scholar 

  13. Kapp JA, Kapp LM, McKenna KC, Lake JP (2004) gammadelta T-cell clones from intestinal intraepithelial lymphocytes inhibit development of CTL responses ex vivo. Immunology 111:155–164

    Article  PubMed  CAS  Google Scholar 

  14. Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R (2002) Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 99:14338–14343

    Article  PubMed  CAS  Google Scholar 

  15. Inagaki-Ohara K, Chinen T, Matsuzaki G, Sasaki A, Sakamoto Y, Hiromatsu K, Nakamura-Uchiyama F, Nawa Y, Yoshimura A (2004) Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation. J Immunol 173:1390–1398

    PubMed  CAS  Google Scholar 

  16. Tsuchiya T, Fukuda S, Hamada H, Nakamura A, Kohama Y, Ishikawa H, Tsujikawa K, Yamamoto H (2003) Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol 171:5507–5513

    PubMed  CAS  Google Scholar 

  17. Kuhl AA, Pawlowski NN, Grollich K, Loddenkemper C, Zeitz M, Hoffmann JC (2007) Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models. J Leukoc Biol 81:168–175

    Article  PubMed  Google Scholar 

  18. Faria AM, Weiner HL (2005) Oral tolerance. Immunol Rev 206:232–259

    Article  PubMed  CAS  Google Scholar 

  19. Hyun JG, Barrett TA (2006) Oral tolerance therapy in inflammatory bowel disease. Am J Gastroenterol 101:569–571

    Article  PubMed  CAS  Google Scholar 

  20. Trentham DE (1998) Oral tolerization as a treatment of rheumatoid arthritis. Rheum Dis Clin North Am 24:525–536

    Article  PubMed  CAS  Google Scholar 

  21. von Herrath MG, Dyrberg T, Oldstone MB (1996) Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice. J Clin Invest 98:1324–1331

    Article  Google Scholar 

  22. Ilan Y, Gotsman I, Pines M, Beinart R, Zeira M, Ohana M, Rabbani E, Engelhardt D, Nagler A (2000) Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model. Blood 95:3613–3619

    PubMed  CAS  Google Scholar 

  23. Whitacre CC, Gienapp IE, Meyer A, Cox KL, Javed N (1996) Oral tolerance in experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 778:217–227

    Article  PubMed  CAS  Google Scholar 

  24. Ilan Y, Weksler-Zangen S, Ben-Horin S, Diment J, Sauter B, Rabbani E, Engelhardt D, Chowdhury NR, Chowdhury JR, Goldin E (2000) Treatment of experimental colitis by oral tolerance induction: a central role for suppressor lymphocytes. Am J Gastroenterol 95:966–973

    Article  PubMed  CAS  Google Scholar 

  25. Gotsman I, Shlomai A, Alper R, Rabbani E, Engelhardt D, Ilan Y (2001) Amelioration of immune-mediated experimental colitis: tolerance induction in the presence of preexisting immunity and surrogate antigen bystander effect. J Pharmacol Exp Ther 297:926–932

    PubMed  CAS  Google Scholar 

  26. Dasgupta A, Kesari KV, Ramaswamy KK, Amenta PS, Das KM (2001) Oral administration of unmodified colonic but not small intestinal antigens protects rats from hapten-induced colitis. Clin Exp Immunol 125:41–47

    Article  PubMed  CAS  Google Scholar 

  27. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694–702

    PubMed  CAS  Google Scholar 

  28. Cooper HS, Murthy SN, Shah RS, Sedergran DJ (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 69:238–249

    PubMed  CAS  Google Scholar 

  29. Dieleman LA, Palmen MJ, Akol H, Bloemena E, Pena AS, Meuwissen SG, Van Rees EP (1998) Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol 114:385–391

    Article  PubMed  CAS  Google Scholar 

  30. Resendiz-Albor AA, Esquivel R, Lopez-Revilla R, Verdin L, Moreno-Fierros L (2005) Striking phenotypic and functional differences in lamina propria lymphocytes from the large and small intestine of mice. Life Sci 76:2783–2803

    Article  PubMed  CAS  Google Scholar 

  31. Ye Y, Jin X, Yue M, Chen SH, Yu CH, Li YM (2010) The protective effect of oral colitis-derived proteins in a murine model of inflammatory bowel disease is associated with an increase in γδ T cells in large intestinal mucosa. Int J Colorectal Dis 25:1055–1062

    Article  PubMed  Google Scholar 

  32. Buzoni-Gatel D, Debbabi H, Moretto M, Dimier-Poisson IH, Lepage AC, Bout DT, Kasper LH (1999) Intraepithelial lymphocytes traffic to the intestine and enhance resistance to Toxoplasma gondii oral infection. J Immunol 162:5846–5852

    PubMed  CAS  Google Scholar 

  33. Hoffmann JC, Pawlowski NN, Grollich K, Loddenkemper C, Zeitz M, Kuhl AA (2008) Gammadelta T lymphocytes: a new type of regulatory T cells suppressing murine 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. Int J Colorectal Dis 23:909–920

    Article  PubMed  Google Scholar 

  34. Pomie C, Menager-Marcq I, van Meerwijk JP (2008) Murine CD8+ regulatory T lymphocytes: the new era. Hum Immunol 69:708–714

    Article  PubMed  CAS  Google Scholar 

  35. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27

    Article  PubMed  CAS  Google Scholar 

  36. Sydora BC, Mixter PF, Holcombe HR, Eghtesady P, Williams K, Amaral MC, Nel A, Kronenberg M (1993) Intestinal intraepithelial lymphocytes are activated and cytolytic but do not proliferate as well as other T cells in response to mitogenic signals. J Immunol 150:2179–2191

    PubMed  CAS  Google Scholar 

Download references

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Correspondence to Youming Li.

Additional information

This work was supported by Grant Y2110864 from Natural Science Foundation of Zhejiang Province.

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Ye, Y., Yue, M., Jin, X. et al. The effect of oral tolerance on the roles of small intestinal intraepithelial lymphocytes in murine colitis induced by dextran sodium sulfate. Int J Colorectal Dis 27, 583–593 (2012). https://doi.org/10.1007/s00384-011-1354-x

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  • DOI: https://doi.org/10.1007/s00384-011-1354-x

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