Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection.
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.
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile.
Carolina
C
Moore
Gabriela
G
Tejon
Camila
C
Fuentes
Yessia
Y
Hidalgo
Maria R
MR
Bono
Paula
P
Maldonado
Ricardo
R
Fernandez
Kathryn J
KJ
Wood
Juan A
JA
Fierro
Mario
M
Rosemblatt
Daniela
D
Sauma
Andrew
A
Bushell
D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage; D012867:Skin / Q000166:cytology / Q000276:immunology*; D016038:Skin Transplantation; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D010047:Ovalbumin
Allogeneic regulatory T cells; Homing; Retinoic acid; Tolerance; Transplantation