Transforming Growth Factor Beta Induced FoxP3+ Regulatory T Cells Suppress Th1 Mediated Experimental Colitis

Overview

Journal Gut

Specialty Gastroenterology

Date 2005 Sep 16

PMID 16162681

Citations 95

Authors

M C Fantini

C Becker

I Tubbe

A Nikolaev

H A Lehr

P Galle

M F Neurath

Affiliations

Soon will be listed here.

Abstract

Background And Aims: The imbalance between effector and regulatory T cells plays a central role in the pathogenesis of inflammatory bowel diseases. In addition to the thymus, CD4+CD25+ regulatory T cells can be induced in the periphery from a population of CD25- T cells by treatment with transforming growth factor beta (TGF-beta). Here, we analysed the in vivo function of TGF-beta induced regulatory T (Ti-Treg) cells in experimental colitis.

Methods: Ti-Treg cells were generated in cell culture in the presence or absence of TGF-beta and tested for their regulatory potential in experimental colitis using the CD4+CD62L+ T cell transfer model.

Results: Ti-Treg cells significantly suppressed Th1 mediated colitis on CD4+CD62L+ T cell transfer in vivo, as shown by high resolution endoscopy, histology, immunohistochemistry, and cytokine analysis. Further analysis of in vivo and in vitro expanded Ti-Treg cells showed that exogenous interleukin 2 (IL-2) was crucial for survival and expansion of these cells.

Conclusion: Our data suggest that regulatory Ti-Treg cells expand by TGF-beta and exogenous IL-2 derived from effector T cells at the site of inflammation. In addition to Tr1 and thymic CD4+CD25+ T cells, peripheral Ti-Treg cells emerge as a class of regulatory T cells with therapeutic potential in T cell mediated chronic intestinal inflammation.

Citing Articles

Interaction of semen with female reproductive tract tissues: what we know, what we guess and what we need to do.

Bromfield J Anim Reprod. 2024; 21(3):e20240042.

PMID: 39176000 PMC: 11340795. DOI: 10.1590/1984-3143-AR2024-0042.

Cellular immunotherapies and immune cell depleting therapies in inflammatory bowel diseases: the next magic bullet?.

Neurath M, Sands B, Rieder F Gut. 2024; 74(1):9-14.

PMID: 39025492 PMC: 11671923. DOI: 10.1136/gutjnl-2024-332919.

Strategies for targeting cytokines in inflammatory bowel disease.

Neurath M Nat Rev Immunol. 2024; 24(8):559-576.

PMID: 38486124 DOI: 10.1038/s41577-024-01008-6.

Exploring Colitis through Dynamic T Cell Adoptive Transfer Models.

Yang W, Cong Y Inflamm Bowel Dis. 2023; 29(10):1673-1680.

PMID: 37536274 PMC: 10547233. DOI: 10.1093/ibd/izad160.

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes.

Atreya I, Neurath M Biomedicines. 2022; 10(11).

PMID: 36428508 PMC: 9687992. DOI: 10.3390/biomedicines10112940.

References

van Montfrans C, Hooijberg E, Rodriguez Pena M, de Jong E, Spits H, Te Velde A . Generation of regulatory gut-homing human T lymphocytes using ex vivo interleukin 10 gene transfer. Gastroenterology. 2002; 123(6):1877-88. DOI: 10.1053/gast.2002.37066. View

Fantini M, Becker C, Monteleone G, Pallone F, Galle P, Neurath M . Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172(9):5149-53. DOI: 10.4049/jimmunol.172.9.5149. View

Kyewski B, Derbinski J . Self-representation in the thymus: an extended view. Nat Rev Immunol. 2004; 4(9):688-98. DOI: 10.1038/nri1436. View

Groux H, Powrie F . Regulatory T cells and inflammatory bowel disease. Immunol Today. 1999; 20(10):442-5. DOI: 10.1016/s0167-5699(99)01510-8. View

Zeller J, Panoskaltsis-Mortari A, Murphy W, Ruscetti F, Narula S, Roncarolo M . Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta. J Immunol. 1999; 163(7):3684-91. View

Groux H, OGarra A, Bigler M, Rouleau M, Antonenko S, De Vries J . A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997; 389(6652):737-42. DOI: 10.1038/39614. View

Curotto de Lafaille M, Lino A, Kutchukhidze N, Lafaille J . CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J Immunol. 2004; 173(12):7259-68. DOI: 10.4049/jimmunol.173.12.7259. View

Becker C, Fantini M, Wirtz S, Nikolaev A, Kiesslich R, Lehr H . In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy. Gut. 2005; 54(7):950-4. PMC: 1774595. DOI: 10.1136/gut.2004.061283. View

Neurath M, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H . The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J Exp Med. 2002; 195(9):1129-43. PMC: 2193714. DOI: 10.1084/jem.20011956. View

10.

Becker C, Fantini M, Schramm C, Lehr H, Wirtz S, Nikolaev A . TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 2004; 21(4):491-501. DOI: 10.1016/j.immuni.2004.07.020. View

11.

Blumberg R, Saubermann L, Strober W . Animal models of mucosal inflammation and their relation to human inflammatory bowel disease. Curr Opin Immunol. 2000; 11(6):648-56. DOI: 10.1016/s0952-7915(99)00032-1. View

12.

MacDonald T, Monteleone G, Pender S . Recent developments in the immunology of inflammatory bowel disease. Scand J Immunol. 2000; 51(1):2-9. DOI: 10.1046/j.1365-3083.2000.00658.x. View

13.

Breese E, Braegger C, Corrigan C, Walker-Smith J, MacDonald T . Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology. 1993; 78(1):127-31. PMC: 1421783. View

14.

Itoh M, Takahashi T, Sakaguchi N, KUNIYASU Y, Shimizu J, Otsuka F . Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol. 1999; 162(9):5317-26. View

15.

OGarra A, Vieira P . Twenty-first century Foxp3. Nat Immunol. 2003; 4(4):304-6. DOI: 10.1038/ni0403-304. View

16.

Powrie F, Carlino J, Leach M, Mauze S, Coffman R . A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996; 183(6):2669-74. PMC: 2192626. DOI: 10.1084/jem.183.6.2669. View

17.

Powrie F, Maloy K . Immunology. Regulating the regulators. Science. 2003; 299(5609):1030-1. DOI: 10.1126/science.1082031. View

18.

Gavin M, Clarke S, Negrou E, Gallegos A, Rudensky A . Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol. 2001; 3(1):33-41. DOI: 10.1038/ni743. View

19.

Podolsky D . The current future understanding of inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 2002; 16(6):933-43. DOI: 10.1053/bega.2002.0354. View

20.

Monteleone G, MacDonald T, Wathen N, Pallone F, Pender S . Enhancing Lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury. Gastroenterology. 1999; 117(5):1069-77. DOI: 10.1016/s0016-5085(99)70391-4. View