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RESEARCH PRODUCT
Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression.
Massimo FantiniChristoph BeckerMassimiliano SarraThomas T. MacdonaldGiovanni MonteleoneAngelamaria RizzoCarmine StolfiFrancesco PalloneMarkus F. NeurathDaniele FinaRoberta Carusosubject
antisense oligonucleotideCD4-Positive T-LymphocytesAdoptive cell transferT-Lymphocytesanimal cellCell CommunicationInbred C57BLT-Lymphocytes RegulatoryTransgenicMiceregulatory T lymphocyteCrohn DiseaseTransforming Growth Factor betamononuclear cellRAG1 proteinIntestinal MucosaenteritisCells CulturedMice KnockoutSettore MED/12 - GastroenterologiaCulturedintegumentary systemmedicine.diagnostic_testarticleGastroenterologyInterleukinhemic and immune systemsT helper cellColitisRegulatoryUp-Regulationmedicine.anatomical_structurepriority journalgamma interferonSignal TransductionRegulatory T cellColonCellsKnockoutanimal experimentinterleukin 6chemical and pharmacologic phenomenaMice TransgenicBiologyinterleukin 2Recombination-activating geneFlow cytometryProinflammatory cytokineSmad7 ProteinmedicineAnimalsHumanscontrolled studyhumanlamina propriamouseCell ProliferationHomeodomain ProteinsCD4+ T lymphocytenonhumanHepatologyAnimalflow cytometryhuman cellanimal cell culturetransgenic mouseMice Inbred C57BLDisease Models Animalantisense oligonucleotide; gamma interferon; interleukin 17; interleukin 2; interleukin 6; RAG1 protein; Smad7 protein; animal cell; animal cell culture; animal experiment; article; CD4+ T lymphocyte; cell proliferation; colitis; controlled study; enteritis; flow cytometry; human; human cell; knockout mouse; lamina propria; mononuclear cell; mouse; nonhuman; priority journal; regulatory T lymphocyte; transgenic mouse; Animals; CD4-Positive T-Lymphocytes; Cell Communication; Cell Proliferation; Cells Cultured; Colitis; Colon; Crohn Disease; Disease Models Animal; Homeodomain Proteins; Humans; Intestinal Mucosa; Mice; Mice Inbred C57BL; Mice Knockout; Mice Transgenic; Signal Transduction; Smad7 Protein; T-Lymphocytes Regulatory; Transforming Growth Factor beta; Up-RegulationDisease ModelsImmunologyinterleukin 17knockout mouseTransforming growth factordescription
Background & Aims 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)-β signaling is required for their function. In inflammatory bowel disease (IBD), the TGF-β 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 naive 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2008-09-17 | Gastroenterology |