Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation

BMC Gastroenterol. 2012 Jul 31;12:97. doi: 10.1186/1471-230X-12-97.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / metabolism*
  • Colitis / pathology
  • Cytokines / biosynthesis
  • Dextran Sulfate / pharmacology
  • Diphtheria Toxin / pharmacology
  • Forkhead Transcription Factors / analysis
  • Heparin-binding EGF-like Growth Factor
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Homeodomain Proteins / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intestinal Mucosa / metabolism
  • Lymphocyte Depletion*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pneumonia / chemically induced
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Severity of Illness Index
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Cytokines
  • Diphtheria Toxin
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • RAG-1 protein
  • Dextran Sulfate