Retinoic acid attenuates acute heart rejection by increasing regulatory T cell and repressing differentiation of Th17 cell in the presence of TGF-β.
Retinoic acid (RA), in a transforming growth factor beta (TGF-β)-dependent manner, promotes differentiation of regulatory T cells (Tregs) but inhibits the differentiation of Th17 cells in vitro from naive CD4(+) T cells. In addition, transfer of induced Tregs (iTregs) reduces rejection. We therefore examined whether RA could attenuate acute cardiac transplant rejection in vivo in a mouse model by regulating the reciprocal differentiation of Tregs and Th17 cells. The iTregs and naive T cells were respectively transferred into congenic mice. Two weeks later, the percentages of transferred cells and Forkhead box P3 (FoxP3)+ Tregs were measured in spleen. Mice with cardiac transplants were treated with TGF-β alone, RA alone, both or none. The percentage of Tregs or Th17 cells in CD4(+) T cells, the level of FoxP3 protein or serous interleukin (IL)-17A, or suppressive function of Tregs from recipient mice were assessed. The percentage of Th17 cells and level of serum IL-17A both increased significantly during acute rejection. RA favored differentiation to Tregs over Th17 cells. Unlike naive T cells, only a few transferred iTregs remained after transfer. Treatment with RA plus TGF-β prolonged graft survival, increased the percentage of Tregs, and decreased the percentage of Th17 cells in peripheral T cells. Tregs from all recipients had normal suppressive function. In conclusion, treatment with RA plus TGF-β attenuates acute rejection by promoting the differentiation of Tregs and inhibiting the differentiation of Th17 cells.
Wang
Guohua
G
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Zhong
Aimei
A
Wang
Sihua
S
Dong
Nianguo
N
Sun
Zongquan
Z
Xia
Jiahong
J
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000502:physiology; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation; D008297:Male; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014212:Tretinoin / Q000627:therapeutic use*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D014212:Tretinoin