Transforming growth factor-β1-induced CD4+CD25+ regulatory T cells in vitro reverse and prevent a murine lupus-like syndrome of chronic graft-versus-host disease

Abstract

BACKGROUND: The suppressive mechanism of CD4+CD25+ regulatory T cells (Tregs) is poorly understood. It is also not known how to obtain enough peripheral Tregs, and how to make them effective in ameliorating a murine lupus-like syndrome of chronic graft-versus-host disease (cGVHD). OBJECTIVES: To confirm the contribution of transforming growth factor (TGF)-beta1 in the function of CD4+CD25+ Tregs in vitro, and to identify in vivo suppressive effects of different Tregs generated through TGF-beta1. METHODS: Suppressive effects of freshly isolated CD4+CD25+ Tregs, TGF-beta1-expanded CD4+CD25+ Tregs (eTregs) and TGF-beta1-induced CD4+CD25+ Tregs (iTregs) in vitro were assessed. Reverse transcription-polymerase chain reaction was used to detect Foxp3. The respective roles that different Tregs might play in controlling murine lupus-like syndrome of cGVHD were analysed. RESULTS: TGF-beta1 was necessary for expanding the existing CD4+CD25+ Tregs in vitro, as well as converting peripheral CD4+CD25- T cells to CD4+CD25+ Tregs through upregulating CD25 and Foxp3. These eTregs and iTregs had a suppressive effect similar to that of freshly isolated CD4+CD25+ Tregs. The inhibitory function of iTregs could be partially blocked by anti-TGF-beta1. Importantly, it was revealed for the first time that both eTregs and iTregs had an inhibitory effect on reversing the morbidity of mice that had already developed anti-dsDNA, and iTregs gave more suppression than eTregs. Besides, iTregs could prevent the onset and slow the progress of disease in a significantly dose-dependent manner. CONCLUSIONS: Results indicate that TGF-beta1 signalling is required to maintain the suppression of CD4+CD25+ Tregs in vitro and in vivo. Together, this study suggests a possible therapeutic role for iTregs in the treatment of murine lupus-like syndrome of cGVHD.

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