title: Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression.
abstract: OBJECTIVE
  Foxp3-expressing regulatory T cells (Tregs) play a key role in the maintenance of the gut immune homeostasis, and an intact transforming growth factor (TGF)-beta signaling is required for their function. In inflammatory bowel disease (IBD), the TGF-beta signaling is impaired because of high expression of the inhibitory molecule Smad7. Although no intrinsic defects in Tregs function have been shown in IBD, it is still unknown whether colitogenic T cells are susceptible to Treg-mediated suppression. In this study, we have investigated whether IBD mucosal CD4+ T cells are resistant to Tregs and whether Smad7 is involved in this process.
  
  
  METHODS
  IBD lamina propria mononuclear cells (LPMC) were cultured with or without Tregs, and proliferation was assessed by flow cytometry. Proliferation of IBD LPMC was also evaluated after Smad7 antisense oligonuclotide treatment. Treg-mediated suppression of T-cell proliferation and proinflammatory cytokine expression was investigated in murine Smad7 transgenic cells. In vivo, the Smad7-dependent resistance of colitogenic naïve T cells to Tregs was studied in the adoptive transfer model of colitis.
  
  
  RESULTS
  IBD LPMC were resistant to Treg-mediated suppression, and this phenomenon was reverted by Smad7 antisense treatment. Consistently, CD4+ T cells isolated from Smad7 transgenic mice showed high proliferation, produced considerable amount of inflammatory cytokines following activation, and induced a severe colitis when transferred in immunodeficient RAG1 knockout mice even in the presence of wild-type Tregs.
  
  
  CONCLUSIONS
  Smad7 makes CD4+ T cells resistant to Tregs-mediated suppression thus fine-tuning their proinflammatory potential.
authors.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Massimo C
authors.initials: MC
authors.lastname: Fantini
authors.forename: Angelamaria
authors.initials: A
authors.lastname: Rizzo
authors.forename: Daniele
authors.initials: D
authors.lastname: Fina
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sarra
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Macdonald
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000378:metabolism* / Q000473:pathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein