Abstract
BackgroundMice 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.MethodsFoxp3-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.ResultsContinuous 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.ConclusionIntermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.
Highlights
Mice lacking Foxp3+ regulatory T (Treg) cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed
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
For the experiments presented in this manuscript we used Foxp3-green fluorescent protein (GFP)-diphtheria toxin receptor (DTR) mice on a C57BL/6 background [2,3]
Summary
Mice lacking Foxp3+ regulatory T (Treg) cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. Regulatory T cells expressing the forkhead family transcription factor Foxp play a or immunomodulatory properties, Foxp3-expressing Treg represent the only currently known population of lymphocytes acting as dedicated mediators of dominant tolerance, whose suppressor function is vital for the maintenance of immune homeostasis. The immune response in the intestine is a tightly controlled balance between innate and adaptive effector responses and negative regulatory pathways of control [11,12,13,14]. Disruption of this balance by genetic or environmental factors can lead to chronic inflammatory syndromes such as the inflammatory bowel diseases (IBDs). Disease development can be prevented and cured by transfer of CD4+CD25+ Treg cells, providing a tractable model to unravel factors controlling the accumulation and function of colitogenic T cells and Treg cells in vivo [15]
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