Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 45, Issue 2, Pages 452-463Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201444743
Keywords
Allogeneic regulatory T cells; Homing; Retinoic acid; Tolerance; Transplantation
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Funding
- FONDECYT [1100557, 1100448, 1120731]
- CONICYT [PFB16]
- MECESUP [UCH-0713]
- British Heart Foundation [PG/10/62/28504] Funding Source: researchfish
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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-beta. 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-beta, 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-beta, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation.
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