Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation

• DOI: 10.1073/pnas.1922600117
• Publication Date: 2020-05-16T00:16:48Z
• Authors: Norihisa Mikami; Ryoji Kawakami; Kelvin Y. Chen; Atsushi Sugimoto; Naganari Ohkura; Shimon Sakaguchi
• Keywords: CD80; CD86; Adoptive Cell Transfer

Foxp3-expressing regulatory T cells (Tregs) can be generated in vitro by antigenic stimulation of conventional (Tconvs) the presence TGF-β and IL-2. However, unlike Foxp3 + naturally occurring Tregs, such induced Tregs (iTregs) are functionally unstable mainly because incomplete Treg-type epigenetic changes at Treg signature genes as . Here we show that deprivation CD28 costimulatory signal an early stage iTreg generation is able to establish Treg-specific DNA hypomethylation genes. It was achieved, for example, TCR/TGF-β/IL-2 CD28-deficient Tconvs or CD28-intact without anti-CD28 agonistic mAb with CD80/CD86-blocked -deficient antigen-presenting cells. The abrogation could induce memory/effector well naive Tconvs, while hindering Tconv differentiation into effector Among various cytokines activators/inhibitors, TNF-α PKC agonists inhibited hypomethylation. Furthermore, significantly reduced c-Rel expression iTregs; specific genomic perturbation a NF-κB binding motif CNS2 locus enhanced locus-specific even signaling-intact iTregs. In addition, maintenance epigenome-installed iTregs IL-2 alone, additional stimulation, enabled their expansion stabilization These indeed stably expressed after vivo transfer effectively suppressed antigen-specific immune responses. Taken together, inhibition CD28-PKC-NF-κB signaling pathway enables de novo acquisition abundant production stable therapeutic purposes.