Inflammatory CD4⁺ T cells can waive NRF2-dependent SLC7A11-mediated cystine uptake by using ASCT1

Ferroptosis and lipid peroxidation are associated with inflammatory and pathogenic conditions. However, cell-specific mechanisms and functions are not fully understood. Cysteine is an essential amino acid for T cell activation and proliferation and is required to synthesize glutathione, the most abundant antioxidant molecule in cells. Cysteine is predominantly produced intracellularly after uptake of its oxidized form (cystine) by SLC7A11. In this study, we provide a detailed analysis of lipid peroxidation in human T cells and analyzed functional consequences in the chronic inflammatory condition of childhood arthritis. We found that healthy peripheral blood CD4 T cells are not fully dependent on SLC7A11 expression and cystine uptake to prevent ferroptotic cell death, most likely by switching to ASCT1-mediated cysteine uptake. T cells from patients with JIA have a high ASCT1 expression, which most likely prevents exaggerated lipid peroxidation and enables them to maintain their inflammatory phenotype in challenging environments such as inflamed joints.