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CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3(+) T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation.

Original publication

DOI

10.1002/eji.201444743

Type

Journal article

Journal

Eur J Immunol

Publication Date

02/2015

Volume

45

Pages

452 - 463

Keywords

Allogeneic regulatory T cells, Homing, Retinoic acid, Tolerance, Transplantation, Adoptive Transfer, Allografts, Animals, Coculture Techniques, Dendritic Cells, Forkhead Transcription Factors, Gene Expression, Graft Rejection, Graft Survival, Interleukin-2, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Ovalbumin, Skin, Skin Transplantation, Spleen, T-Lymphocytes, Regulatory, Transforming Growth Factor beta, Tretinoin