Retinoic acid attenuates acute heart rejection by increasing regulatory T cell and repressing differentiation of Th17 cell in the presence of TGF-β

Abstract

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.