Sulfur partitioning from cysteine controls T cell proliferation and effector function

Delineating how acquired nutrients are partitioned into different intracellular pathways and how these various fates support distinct functions in T cells is limited. We show that CD8⁺ T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8⁺ T cells promotes exhaustion and dampens anti-cancer immunity, whereas blocking cysteine flux into GSH or enforcing FeS metabolism enhances tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human hepatocellular carcinoma. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain the beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.