GSE96960
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance
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 the expression of the transcription factor Foxp3, and recent work suggested 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-specific Foxp3+ Tregs (allo-iTregs) in presence of vitamin C, and those Tregs showed a pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes, accompanied with an enhanced stability of Foxp3 expression. However, RNA-seq analysis revealed an only minor impact of Vitamin C on the transcriptome of allo-iTregs. Importantly, when being tested in vivo in a highly immunogenic skin transplantation model vitamin C-treated allo-iTregs showed a superior suppressive capacity as compared to allo-iTregs generated in absence of vitamin C. Together, our results might pave the way for the establishment of novel protocols for the in vitro generation of allo-antigen specific Foxp3+ Tregs for therapeutic usage in transplantation medicine. Overall design: FACS sorted allo-iTregs (CD4+CD90.2+Foxp3RFP+) from cultures in presence or absence of vitamin C