Tbet Expression in Regulatory T Cells Is Required to Initiate Th1-Mediated Colitis: Frontiers in Immunology

M. Di Giovangiulio, A. Rizzo, E. Franzè, F. Caprioli, F. Facciotti, S. Onali, A. Favale, C. Stolfi, H.-J. Fehling, G. Monteleone, M.C. Fantini

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Abstract

In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut. © Copyright © 2019 Di Giovangiulio, Rizzo, Franzè, Caprioli, Facciotti, Onali, Favale, Stolfi, Fehling, Monteleone and Fantini.
Original languageEnglish
JournalFront. Immunol.
Volume10
DOIs
Publication statusPublished - 2019

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Keywords

  • inflammation
  • inflammatory bowel disease
  • Tbet
  • Th1-like Tregs
  • Treg cells
  • CD45RB antigen
  • gamma interferon
  • interleukin 10
  • interleukin 12p35
  • interleukin 17
  • interleukin 22
  • interleukin 23p19
  • interleukin 6
  • transcription factor FOXP3
  • transcription factor T bet
  • tumor necrosis factor
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • CD3+ T lymphocyte
  • CD4+ T lymphocyte
  • cell proliferation
  • cell proliferation assay
  • cell subpopulation
  • clinical article
  • controlled study
  • cytokine release
  • disease course
  • disease severity
  • experimental colitis
  • flow cytometry
  • gene expression
  • gene knockout
  • histopathology
  • human
  • immune response
  • male
  • mouse
  • nonhuman
  • protein expression
  • real time polymerase chain reaction
  • regulatory T lymphocyte
  • T lymphocyte activation
  • Th1 cell
  • ulcerative colitis
  • upregulation

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