Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection |
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Authors: | Carolina Moore Gabriela Tejon Camila Fuentes Yessia Hidalgo Maria R Bono Paula Maldonado Ricardo Fernandez Kathryn J Wood Juan A Fierro Mario Rosemblatt Daniela Sauma Andrew Bushell |
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Institution: | 1. Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile;2. Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile;3. Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK;4. Unidad de Trasplantes, Clinica las Condes, Santiago, Chile;5. Fundacion Ciencia y Vida, Santiago, Chile |
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Abstract: | 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. |
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Keywords: | Allogeneic regulatory T  cells Homing Retinoic acid Tolerance Transplantation |
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