Cysteine reactivity profiling links metabolic rewiring to the dysfunctional human T cell proteome.

Cysteine reactivity profiling uncovers metabolic rewiring that impairs T cell function, with significant changes linked to stress pathways and ATP depletion in dysfunctional human T cells.

• Why it matters: Understanding post-translational modifications in T cell dysfunction is crucial for developing therapies to restore immune responses in chronic infections and cancer, where T cells lose their cytotoxic ability.
• What they did: The study used proteomic and cysteine reactivity profiling on human T cells experiencing chronic antigen exposure, identifying stress pathway activation and nucleotide-binding protein alterations, especially involving MAP2K4.
• The result: Targeting MAP2K4 reactivated T cell cytotoxicity, demonstrating that metabolic and post-translational changes can be therapeutically modulated, paving the way for cysteine-based treatments to improve cancer immunotherapy.