Regulatory T cells (Treg) are critical regulators of immune homeostasis. Increasing evidence demonstrates that environment-driven Treg differentiation into effector Treg is crucial for optimal functioning. However, programming of human Treg under inflammatory conditions remains poorly understood. Here, we combine transcriptional and epigenetic profiling to identify the human effector Treg core signature. Autoimmune inflammation-derived Treg demonstrated normal suppressive function and enhanced IL-2 signaling. Transcriptome analysis revealed a unique transcriptional profile characterized by upregulation of both a core Treg (FOXP3, CTLA-4, TIGIT) and effector program (ICOS, GITR, BLIMP-1, BATF, T-bet), indicating effector Treg differentiation and adaptation to the inflammatory environment. We identified specific human effector Treg markers including VDR and IL12Rβ2. H3K27ac occupancy revealed large changes in the (super-)enhancer landscape, including enrichment of the binding motif for VDR and BATF. The observed Treg profile showed striking overlap with tumor-infiltrating Treg. Our data demonstrate that human inflammation-derived Treg acquire a specific effector Treg profile guided by epigenetic changes. The core effector Treg profile is strongly conserved, and fine-tuned by environment specific adaptations.