Fig. 5. The network of redox signaling for determining the fate of T cells. (A) Superoxide radicals are generated at various subcellular spaces and undergo enzymatic conversion into H₂O₂ by superoxide dismutase (SOD). Glutathione (GSH) reduces H₂O₂ levels by converting it into water. Upon T cell receptor (TCR) stimulation, NOX becomes activated to generate H₂O₂. H₂O₂ selectively oxidizes thiol groups on the surface or cytosol of T cells, modulating diverse cellular processes, including DNA synthesis, epigenetic regulation and post-translational modifications. Cysteine from antigen-presenting cells (APCs) is resorbed by T cells and assimilated into an enzymatic process generating GSH. GSH preserves the reduced status of thiol on the surface of the cell, mitigating H₂O₂ effects. Thioredoxin (TRX) synthesized by T cells, APCs, and Tregs contribute to maintaining the thiol group on the cell surface. (B) Antigen-stimulated T cells express active NOX that generates reactive oxygen species (ROS) in the cytosol. ROS induce conformational changes in Keap1, which leads to Nrf2 translocation into the nucleus. Nrf2 binds to antioxidant response elements (AREs) in the promoter region of glutamate-cysteine ligase catalytic subunit (GCLC) catalyzing GSH synthesis. This figure depicts how NOX, Keap1, and GCLC knock-out affect the function of T cells in various disease conditions. (C) ROS stabilizes SENP3 that drives deSUMOylation of BACH2, which potentiates Tregs expansion through enhancing Foxp3 expression. Moreover, ROS mediates H3K27 acetylation at Foxp3 promoter, which accelerates the transcription of Foxp3 gene. Conversely, mitochondrial ROS accumulation in autoimmune conditions causes DNA damage in Tregs, causing the death of Tregs. NOX: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase.