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Abstract
Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen-induced Foxp3+ Tregs (allo-iTregs) in presence of vitamin C. Although vitamin C hardly influenced the transcriptome of allo-iTregs as revealed by RNA-seq, those vitamin C-treated allo-iTregs showed a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes accompanied with an enhanced stability of Foxp3 expression. Accordingly, when being tested in vivo in an allogeneic skin transplantation model, vitamin C-treated allo-iTregs showed a superior suppressive capacity. Together, our results pave the way for the establishment of novel protocols for the in vitro generation of alloantigen-induced Foxp3+ Tregs for therapeutic use in transplantation medicine.
Highlights
Regulatory T cells (Tregs) play an important role for the maintenance of immune homeostasis and self-tolerance [1, 2]
When forkhead box P3 (Foxp3) expression was analyzed in cultured T cells by flow cytometry at day 6, we observed that the addition of vitamin C led to a small, but significant increase in the frequency of Foxp3+ allo-iTregs when compared to cultures without vitamin C (Figures 1A,B)
These findings suggest that vitamin C fosters the in vitro generation of allo-iTregs leading to a higher frequency of Tregs that express higher levels of Foxp3 protein
Summary
Regulatory T cells (Tregs) play an important role for the maintenance of immune homeostasis and self-tolerance [1, 2]. In vitro generation of polyclonal or alloantigen-specific Foxp3+ Tregs can be achieved by appropriate TCR stimulation of conventional Foxp3−CD4+ T cells in presence of TGF-β and IL-2 (in vitro induced Tregs, iTregs) [19]. These iTregs display an unstable Treg phenotype and rapidly lose Foxp expression and suppressive activity upon in vitro re-stimulation in the absence of TGF-β or upon adoptive transfer [20,21,22]. Clinical use of iTregs remains critical as these cells might even convert into effector T cells, potentially exerting negative effects for the patient
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