Patients with the neurological disorder HSAN-I suffer frequent infections， attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8 T?cells are affected in HSAN-I patients remains unknown. Here， we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T?cell responses. Antigen stimulation and inflammation induced SPTLC2 expression， and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1)， endoplasmic reticulum (ER) s... More
Patients with the neurological disorder HSAN-I suffer frequent infections， attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8 T?cells are affected in HSAN-I patients remains unknown. Here， we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T?cell responses. Antigen stimulation and inflammation induced SPTLC2 expression， and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1)， endoplasmic reticulum (ER) stress， and CD8 T?cell death. Protective CD8 T?cell responses in HSAN-I patient PBMCs and Sptlc2-deficient mice were restored by supplementing with sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Therefore， SPTLC2 underpins protective immunity by translating extracellular stimuli into intracellular anabolic signals and antagonizes ER stress to promote T?cell metabolic fitness.
