The role of interleukin-12-PRMT5 axis in generating suppressive Th1-like induced regulatory T cells

Abstract

Abstract After activation, naïve CD4 T cells can differentiate into T helper cell subsets (Th1, Th2, Th17, and Follicular helper T cells) or into regulatory T cells (Tregs), depending on the type of antigen-presenting cells (APC) and cytokine milieu encountered during differentiation. Recent studies suggest that CD4+Foxp3+ Tregs can produce the pro-inflammatory cytokine IFNg when stimulated in a Th1 cytokine environment, such as in the presence of IL-12, and stimulation under these conditions makes iTregs sensors for inflammatory cytokines. The stability and suppressive functions of the iTregs depend on multiple factors. The goal of this study is to explore an epigenetic enzyme protein arginine methyltransferase 5 (PRMT5) and to understand the significance of this protein in the development of Th1-like iTregs. PRMT5 can either represses or activate transcription of target genes via symmetric di-methylation of arginine residues on histones. However, the role of PRMT5 in the differentiation of Th1-like iTregs has not been thoroughly investigated. We demonstrate that differentiating iTregs in a Th1 cytokine environment generated a specific population of Th1-like iTregs with increased suppressive function. In Th1-like iTregs, we observed symmetric arginine di-methylation on histone (H3R2me2s) mediated by PRMT5, while this epigenetic marker is absent in iTregs. We also demonstrate that si-RNA mediated knockdown of PRMT5 reduced the suppressive capacity of Th1-like iTregs. Therefore, we hypothesize that the IL12-PRMT5 axis is crucial for developing suppressive Th1-like iTregs. Goals of further research are to generate stable immunosuppressive iTregs for therapeutic use.