title: Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation.
abstract: BACKGROUND
  Mice lacking Foxp3+ regulatory T (Treg) cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation.
  
  
  METHODS
  Foxp3-GFP-DTR (human diphtheria toxin receptor) C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin). The influence of Foxp3+ Treg on intestinal inflammation was tested using the CD4+ T-cell transfer colitis model in Rag-/- C57BL/6 mice and the acute DSS-colitis model.
  
  
  RESULTS
  Continuous depletion of Foxp3+ Treg in Foxp3-GFP-DTR mice led to dramatic weight loss and death of mice by day 28. After 10 days of depletion of Foxp3+ Treg, isolated CD4+ T-cells were activated and produced extensive amounts of IFN-γ, IL-13, and IL-17A. Transfer of total CD4+ T-cells isolated from Foxp3-GFP-DTR mice did not result in any changes of intestinal homeostasis in Rag-/- C57BL/6 mice. However, administration of DTx between days 14 and 18 after T-cell reconstitution, lead to elimination of Foxp3+ Treg and to immediate weight loss due to intestinal inflammation. This pro-inflammatory effect of Foxp3+ Treg depletion consecutively increased inflammatory cytokine production. Further, the depletion of Foxp3+ Treg from Foxp3-GFP-DTR mice increased the severity of acute dSS-colitis accompanied by 80% lethality of Treg-depleted mice. CD4+ effector T-cells from Foxp3+ Treg-depleted mice produced significantly more pro-inflammatory cytokines.
  
  
  CONCLUSIONS
  Intermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.
authors: Department of Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg 93053, Germany.
authors: Franziska
authors: F
authors: Boehm
authors: Maria
authors: M
authors: Martin
authors: Rebecca
authors: R
authors: Kesselring
authors: Gabriela
authors: G
authors: Schiechl
authors: Edward K
authors: EK
authors: Geissler
authors: Hans-Jürgen
authors: HJ
authors: Schlitt
authors: Stefan
authors: S
authors: Fichtner-Feigl
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000494:pharmacology; D004167:Diphtheria Toxin / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000032:analysis; D066257:Heparin-binding EGF-like Growth Factor; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C064658:RAG-1 protein; D016264:Dextran Sulfate