Skip to main content

Advertisement

SpringerLink
Log in

γδ T lymphocytes: a new type of regulatory T cells suppressing murine 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background

The intestinal immune system is continuously challenged by antigen without becoming dysregulated. However, injury of the mucosa by, i.e. dextran sulphate sodium causes severe inflammation in γδ T-cell-deficient mice. We therefore asked whether γδ T cells have regulatory functions.

Materials and methods

γδ T cells were isolated from spleens and mesenteric lymph nodes of C57BL/6 wild-type (wt) mice. Proliferation and cytokine secretion of γδ T cells were quantified by [3H] thymidine incorporation and ELISA. Additionally, proliferation of carboxyfluorescein diacetate succinimidylester-labelled CD4+ T cells cocultured with γδ T cells was analysed by flow cytometry. Finally, γδ T cells from wt or interleukin-10 transgenic (IL-10tg) mice were transferred into congenic mice with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis.

Results

γδ T cells were hyporesponsive to CD3/CD28 stimulation and suppressed CD4+ T-cell proliferation (up to 66 ± 7% suppression) in vitro. Further, the preventive transfer of wt or IL-10tg γδ T cells ameliorated TNBS-induced colitis resulting in prolonged survival and reduced histological damage (1.5 ± 0.4 and 1.3 ± 0.2, respectively vs. 3.8 ± 0.3 in untransferred mice, p < 0.05). This was accompanied by reduced TNF-α and increased IL-10 and TGF-β secretion from intestinal and splenic lymphocytes.

Conclusions

Murine γδ T cells are a new type of regulatory T cells in vitro and act protective on mouse TNBS-induced colitis in vivo. Future studies have to define the underlying mechanism and to investigate whether γδ T cells can be used for immunotherapy of human inflammatory bowel disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Cheroutre H, Kronenberg M (2005) Mucosal T lymphocytes–peacekeepers and warriors. Springer Semin Immunopathol 27:147–165

    Article  PubMed  Google Scholar 

  2. Hayday A, Tigelaar R (2003) Immunoregulation in the tissues by gammadelta T cells. Nat Rev Immunol 3:233–242

    Article  PubMed  CAS  Google Scholar 

  3. Hurley BP, McCormick BA (2004) Intestinal epithelial defense systems protect against bacterial threats. Curr Gastroenterol Rep 6:355–361

    Article  PubMed  Google Scholar 

  4. Kronenberg M, Rudensky A (2005) Regulation of immunity by self-reactive T cells. Nature 435:598–604

    Article  PubMed  CAS  Google Scholar 

  5. Pennington DJ, Silva-Santos B, Shires J, Theodoridis E, Pollitt C, Wise EL, Tigelaar RE, Owen MJ, Hayday AC (2003) The inter-relatedness and interdependence of mouse T cell receptor gammadelta+ and alphabeta+ cells. Nat Immunol 4:991–998

    Article  PubMed  CAS  Google Scholar 

  6. Izcue A, Coombes JL, Powrie F (2006) Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 212:256–271

    Article  PubMed  CAS  Google Scholar 

  7. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742

    Article  PubMed  CAS  Google Scholar 

  8. Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302

    Article  PubMed  CAS  Google Scholar 

  9. Lehmann J, Huehn J, de la Rosa M, Maszyna F, Kretschmer U, Krenn V, Brunner M, Scheffold A, Hamann A (2002) Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25− regulatory T cells. Proc Natl Acad Sci USA 99:13031–13036

    Article  PubMed  CAS  Google Scholar 

  10. Das G, Augustine MM, Das J, Bottomly K, Ray P, Ray A (2003) An important regulatory role for CD4+ CD8 alpha alpha T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc Natl Acad Sci USA 100:5324–5329

    Article  PubMed  CAS  Google Scholar 

  11. Fantini MC, Becker C, Tubbe I, Nikolaev A, Lehr HA, Galle P, Neurath MF (2006) Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 55:671–680

    Article  PubMed  CAS  Google Scholar 

  12. Menager-Marcq I, Pomie C, Romagnoli P, van Meerwijk JP (2006) CD8(+)CD28(−) Regulatory T lymphocytes prevent experimental inflammatory bowel disease in mice. Gastroenterology 131:1775–1785

    Article  PubMed  CAS  Google Scholar 

  13. Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6:353–360

    Article  PubMed  CAS  Google Scholar 

  14. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344

    Article  PubMed  CAS  Google Scholar 

  15. 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 

  16. Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, Duchmann R (2005) Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128:1868–1878

    Article  PubMed  CAS  Google Scholar 

  17. Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A (2001) CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 166:3008–3018

    PubMed  CAS  Google Scholar 

  18. Xystrakis E, Dejean AS, Bernard I, Druet P, Liblau R, Gonzalez-Dunia D, Saoudi A (2004) Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation. Blood 104:3294–3301

    Article  PubMed  CAS  Google Scholar 

  19. Zhang D, Yang W, Degauque N, Tian Y, Mikita A, Zheng XX (2007) New differentiation pathway for double-negative regulatory T-cells that regulates the magnitude of immune responses. Blood 109:4071–4079

    Article  PubMed  CAS  Google Scholar 

  20. Sun JB, Raghavan S, Sjoling A, Lundin S, Holmgren J (2006) Oral tolerance induction with antigen conjugated to cholera toxin B subunit generates both Foxp3+ CD25+ and Foxp3−CD25− CD4+ regulatory T cells. J Immunol 177:7634–7644

    PubMed  CAS  Google Scholar 

  21. Hillebrands JL, Whalen B, Visser JT, Koning J, Bishop KD, Leif J, Rozing J, Mordes JP, Greiner DL, Rossini AA (2006) A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3. J Immunol 177:7820–7832

    PubMed  CAS  Google Scholar 

  22. Goodman T, Lefrancois L (1988) Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333:855–858

    Article  PubMed  CAS  Google Scholar 

  23. Ullrich R, Schieferdecker HL, Ziegler K, Riecken EO, Zeitz M (1990) Gamma delta T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium. Cell Immunol 128:619–627

    Article  PubMed  CAS  Google Scholar 

  24. Deusch K, Luling F, Reich K, Classen M, Wagner H, Pfeffer K (1991) A major fraction of human intraepithelial lymphocytes simultaneously expresses the gamma/delta T cell receptor, the CD8 accessory molecule and preferentially uses the V delta 1 gene segment. Eur J Immunol 21:1053–1059

    Article  PubMed  CAS  Google Scholar 

  25. Findly RC, Roberts SJ, Hayday AC (1993) Dynamic response of murine gut intraepithelial T cells after infection by the coccidian parasite Eimeria. Eur J Immunol 23:2557–2564

    Article  PubMed  CAS  Google Scholar 

  26. Boismenu R, Havran WL (1994) Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266:1253–1255

    Article  PubMed  CAS  Google Scholar 

  27. Komano H, Fujiura Y, Kawaguchi M, Matsumoto S, Hashimoto Y, Obana S, Mombaerts P, Tonegawa S, Yamamoto H, Itohara S et al (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 

  28. Ladel CH, Hess J, Daugelat S, Mombaerts P, Tonegawa S, Kaufmann SH (1995) Contribution of alpha/beta and gamma/delta T lymphocytes to immunity against Mycobacterium bovis bacillus Calmette Guerin: studies with T cell receptor-deficient mutant mice. Eur J Immunol 25:838–846

    Article  PubMed  CAS  Google Scholar 

  29. Fujihashi K, McGhee JR, Kweon MN, Cooper MD, Tonegawa S, Takahashi I, Hiroi T, Mestecky J, Kiyono H (1996) Gamma/delta T cell-deficient mice have impaired mucosal immunoglobulin A responses. J Exp Med 183:1929–1935

    Article  PubMed  CAS  Google Scholar 

  30. Ladel CH, Blum C, Kaufmann SH (1996) Control of natural killer cell-mediated innate resistance against the intracellular pathogen Listeria monocytogenes by gamma/delta T lymphocytes. Infect Immun 64:1744–1749

    PubMed  CAS  Google Scholar 

  31. Roberts SJ, Smith AL, West AB, Wen L, Findly RC, Owen MJ, Hayday AC (1996) T-cell alpha beta + and gamma delta + deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc Natl Acad Sci USA 93:11774–11779

    Article  PubMed  CAS  Google Scholar 

  32. King DP, Hyde DM, Jackson KA, Novosad DM, Ellis TN, Putney L, Stovall MY, Van Winkle LS, Beaman BL, Ferrick DA (1999) Cutting edge: protective response to pulmonary injury requires gamma delta T lymphocytes. J Immunol 162:5033–5036

    PubMed  CAS  Google Scholar 

  33. Hayday AC (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026

    Article  PubMed  CAS  Google Scholar 

  34. Moore TA, Moore BB, Newstead MW, Standiford TJ (2000) Gamma delta-T cells are critical for survival and early proinflammatory cytokine gene expression during murine Klebsiella pneumonia. J Immunol 165:2643–2650

    PubMed  CAS  Google Scholar 

  35. Smith AL, Hayday AC (2000) An alphabeta T-cell-independent immunoprotective response towards gut coccidia is supported by gammadelta cells. Immunology 101:325–332

    Article  PubMed  CAS  Google Scholar 

  36. Cipriani B, Borsellino G, Poccia F, Placido R, Tramonti D, Bach S, Battistini L, Brosnan CF (2000) Activation of C–C beta-chemokines in human peripheral blood gammadelta T cells by isopentenyl pyrophosphate and regulation by cytokines. Blood 95:39–47

    PubMed  CAS  Google Scholar 

  37. Tagawa T, Nishimura H, Yajima T, Hara H, Kishihara K, Matsuzaki G, Yoshino I, Maehara Y, Yoshikai Y (2004) Vdelta1+ gammadelta T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice. J Immunol 173:5156–5164

    PubMed  CAS  Google Scholar 

  38. 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 

  39. Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, Craft J, Yin Z (2003) Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 198:433–442

    Article  PubMed  CAS  Google Scholar 

  40. Mammen JM, Matthews JB (2003) Mucosal repair in the gastrointestinal tract. Crit Care Med 31:S532–S537

    Article  PubMed  Google Scholar 

  41. 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 

  42. 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 

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

    Article  PubMed  Google Scholar 

  44. Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K (1996) Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184:2167–2174

    Article  PubMed  CAS  Google Scholar 

  45. Liu H, Hu B, Xu D, Liew FY (2003) CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4. J Immunol 171:5012–5017

    PubMed  CAS  Google Scholar 

  46. Xu D, Liu H, Komai-Koma M, Campbell C, McSharry C, Alexander J, Liew FY (2003) CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J Immunol 170:394–399

    PubMed  CAS  Google Scholar 

  47. Pawlowski NN, Kakirman H, Kuhl AA, Liesenfeld O, Grollich K, Loddenkemper C, Zeitz M, Hoffmann JC (2005) Alpha CD 2 mAb treatment safely attenuates adoptive transfer colitis. Lab Invest 85:1013–1023

    Article  PubMed  CAS  Google Scholar 

  48. Steinhoff U, Klemm U, Greiner M, Bordasch K, Kaufmann SH (1998) Altered intestinal immune system but normal antibacterial resistance in the absence of P-selectin and ICAM-1. J Immunol 160:6112–6120

    PubMed  CAS  Google Scholar 

  49. Hoffmann JC, Peters K, Henschke S, Herrmann B, Pfister K, Westermann J, Zeitz M (2001) Role of T lymphocytes in rat 2,4,6-trinitrobenzene sulphonic acid (TNBS) induced colitis: increased mortality after gammadelta T cell depletion and no effect of alphabeta T cell depletion. Gut 48:489–495

    Article  PubMed  CAS  Google Scholar 

  50. Kuhl AA, Loddenkemper C, Westermann J, Hoffmann JC (2002) Role of gamma delta T cells in inflammatory bowel disease. Pathobiology 70:150–155

    Article  PubMed  Google Scholar 

  51. Toth B, Alexander M, Daniel T, Chaudry IH, Hubbard WJ, Schwacha MG (2004) The role of gammadelta T cells in the regulation of neutrophil-mediated tissue damage after thermal injury. J Leukoc Biol 76:545–552

    Article  PubMed  CAS  Google Scholar 

  52. Ferrarini M, Ferrero E, Dagna L, Poggi A, Zocchi MR (2002) Human gammadelta T cells: a nonredundant system in the immune-surveillance against cancer. Trends Immunol 23:14–18

    Article  PubMed  CAS  Google Scholar 

  53. Pennington DJ, Vermijlen D, Wise EL, Clarke SL, Tigelaar RE, Hayday AC (2005) The integration of conventional and unconventional T cells that characterizes cell-mediated responses. Adv Immunol 87:27–59

    Article  PubMed  CAS  Google Scholar 

  54. Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, Tony HP (2003) Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 102:200–206

    Article  PubMed  CAS  Google Scholar 

  55. Chen J, Niu H, He W, Ba D (2001) Antitumor activity of expanded human tumor-infiltrating gammadelta T lymphocytes. Int Arch Allergy Immunol 125:256–263

    Article  PubMed  CAS  Google Scholar 

  56. Kawaguchi-Miyashita M, Shimada S, Kurosu H, Kato-Nagaoka N, Matsuoka Y, Ohwaki M, Ishikawa H, Nanno M (2001) An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Eur J Immunol 31:980–988

    Article  PubMed  CAS  Google Scholar 

  57. Simpson SJ, Hollander GA, Mizoguchi E, Allen D, Bhan AK, Wang B, Terhorst C (1997) Expression of pro-inflammatory cytokines by TCR alpha beta+ and TCR gamma delta+ T cells in an experimental model of colitis. Eur J Immunol 27:17–25

    Article  PubMed  CAS  Google Scholar 

  58. McMenamin C, Pimm C, McKersey M, Holt PG (1994) Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells. Science 265:1869–1871

    Article  PubMed  CAS  Google Scholar 

  59. Guan H, Zu G, Slater M, Elmets C, Xu H (2002) GammadeltaT cells regulate the development of hapten-specific CD8+ effector T cells in contact hypersensitivity responses. J Invest Dermatol 119:137–142

    Article  PubMed  CAS  Google Scholar 

  60. Girardi M, Lewis J, Glusac E, Filler RB, Geng L, Hayday AC, Tigelaar RE (2002) Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation. J Exp Med 195:855–867

    Article  PubMed  CAS  Google Scholar 

  61. 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 

  62. 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 

  63. Bregenholt S, Brimnes J, Nissen MH, Claesson MH (1999) In vitro activated CD4+ T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts. Clin Exp Immunol 118:228–234

    Article  PubMed  CAS  Google Scholar 

  64. Camoglio L, te Velde AA, de Boer A, ten Kate FJ, Kopf M, van Deventer SJ (2000) Hapten-induced colitis associated with maintained Th1 and inflammatory responses in IFN-gamma receptor-deficient mice. Eur J Immunol 30:1486–1495

    Article  PubMed  CAS  Google Scholar 

  65. Siegmund B, Sennello JA, Lehr HA, Senaldi G, Dinarello CA, Fantuzzi G (2004) Frontline: interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCR gamma delta T cells and interleukin-18-binding protein. Eur J Immunol 34:2356–2364

    Article  PubMed  CAS  Google Scholar 

  66. Wood KJ, Sawitzki B (2006) Interferon gamma: a crucial role in the function of induced regulatory T cells in vivo. Trends Immunol 27:183–187

    Article  PubMed  CAS  Google Scholar 

  67. Seo N, Tokura Y, Takigawa M, Egawa K (1999) Depletion of IL-10- and TGF-beta-producing regulatory gamma delta T cells by administering a daunomycin-conjugated specific monoclonal antibody in early tumor lesions augments the activity of CTLs and NK cells. J Immunol 163:242–249

    PubMed  CAS  Google Scholar 

  68. Shevach EM (2006) From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25:195–201

    Article  PubMed  CAS  Google Scholar 

  69. Jiang S, Lechler RI, He XS, Huang JF (2006) Regulatory T cells and transplantation tolerance. Hum Immunol 67:765–776

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The work of the authors was supported by SFB 633/B3 and SFB 633/Z1, the German competence network on IBD and by a grant from the German Crohn’s and Colitis foundation (DCCV).

Author information

Author notes

  1. Jörg C. Hoffmann

    Present address: Medizinische Klinik I, St. Marienkrankenhaus, Salzburger Str. 15, 67067, Ludwigsahfen, Germany

Authors and Affiliations

  1. Medizinische Klinik I, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Jörg C. Hoffmann, Nina N. Pawlowski, Katja Grollich, Martin Zeitz & Anja A. Kühl

  2. Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Christoph Loddenkemper

Authors
  1. Jörg C. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nina N. Pawlowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katja Grollich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christoph Loddenkemper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin Zeitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anja A. Kühl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jörg C. Hoffmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoffmann, J.C., Pawlowski, N.N., Grollich, K. et al. γδ 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 (2008). https://doi.org/10.1007/s00384-008-0535-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-008-0535-8

Keywords

Search

Navigation