Induced regulatory T cells (iTregs) are a heterogeneous population of immunosuppressive T cells whose therapeutic potential has been explored extensively in the past few years. Our understanding of the mechanisms that drive the phenotype and function of iTregs is still growing. Recent studies show that Treg cells are not terminally differentiated but, rather, show a range of plasticity. Under different environmental conditions, Tregs can acquire T effector-like capacities. Such is the case for Th1-like, Th2-like, Tfh-like, and Th17-like iTregs. In these scenarios, it is important to differentiate between functional plasticity and lineage instability, which can make iTregs either suppressive or pathogenic. Aplastic anemia (AA) is an autoimmune disorder characterized by the immune-mediated destruction of hematopoietic stem and progenitor cells in the bone marrow (BM). This immune-mediated destruction is primarily driven by T cells. In this study, we explored the potential of Th1-like iTregs as a cell-based therapy for AA, the function of an epigenetic enzyme, protein arginine methyltransferase 5 (PRMT5) and sirturin 1 (Sirt1) in suppressive Th1-like iTregs. We confirmed that exposing iTregs to Th1 cytokine (interleukin-12) during early events of differentiation generated a specific population of Th1-like iTregs with increased suppressive function. We also observed increased PRMT5 enzymatic activity, symmetric arginine di-methylation on histone (H3R2me2s), in Th1-like iTregs while this epigenetic marker is downregulated in iTregs. We further investigated the role of H3R2me2s in the gene regulation of Th1-like iTregs through ChIP-sequencing and discovered novel regulation of Sirt1 through PRMT5. PRMT5 acts as a negative regulator of Sirt1 transcription by occupying the gene’s promoter region through H3R2me2s. Knocking down PRMT5 in Th1-like iTreg concomitantly reduced their suppressive capacity, supporting the notion that PRMT5 is important for the superior suppressive capacity and stability of Th1-like iTregs. Conclusively, therapeutic administration of Th1-like iTregs in the mouse model of AA significantly extended their survival. Therefore, Th1-like iTregs may represent a novel therapeutic approach for treating AA.