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.