Generating functionally stable and antigen-specific T_reg cells from effector T cells for cell therapy of inflammatory...

One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T (T_conv) cells into Foxp3⁺ regulatory T (T_reg) cells that are as stably suppressive as naturally occurring T_reg (nT_reg) cells. To achieve the conversion in vitro for mice and humans, we induced high Foxp3 expression in antigen- and interleukin-2 (IL-2)-stimulated T_conv cells by CDK8/19 inhibition. We further established T_reg cell-specific epigenetic changes by depriving CD28 costimulation during in vitro T_reg cell induction to specifically promote the expression of T_reg cell signature genes, especially Foxp3. Repeating this process, with intermittent resting cultures containing IL-2 only, enabled efficient conversion of naïve as well as effector/memory CD4⁺ T_conv cells, including T helper 1 (T_H1), T_H2, and T_H17 cells, into Foxp3⁺ T_reg cells. These induced T_reg (iT_reg) cells were similar to nT_reg cells in transcription and epigenetic modification and were functionally and phenotypically stable in vivo. Moreover, they effectively suppressed inflammatory bowel disease and graft-versus-host disease in mouse models. Adoptive cell therapy with such effector/memory T_conv cell-derived, functionally stable, iT_reg cells may represent a strategy to achieve antigen- and disease-specific treatment of immunological diseases.