Transforming growth factor-beta1-induced CD4+CD25+ regulatory T cells in vitro reverse and prevent a murine lupus-like syndrome of chronic graft-versus-host disease.
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).


OBJECTIVE
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.
Su
H
H
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 69 Meishan Road, Hefei, Anhui 230032, China.
Ye
D-Q
DQ
Wang
B-L
BL
Fang
X-H
XH
Chen
J
J
Wang
Q
Q
Li
W-X
WX
Zhang
N
N
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000628:therapy; D007167:Immunotherapy / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000627:therapeutic use*
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1