Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness
Authors: Wu J, Ma S, Sandhoff R, Ming Y, Hotz-Wagenblatt A, Timmerman V, Bonello-Palot N, Schlotter-Weigel B, Auer-Grumbach M, Seeman P, Löscher WN, Reindl M, Weiss F, Mah E, Weisshaar N, Madi A, Mohr K, Schlimbach T, Velasco Cárdenas RM, Koeppel J, Grünschläger F, Müller L, Baumeister M, Brügger B, Schmitt M, Wabnitz G, Samstag Y, Cui G
CellNetworks People: Brügger Britta
Journal: Immunity. 2019 Mar 23. pii: S1074-7613(19)30095-0. doi: 10.1016/j.immuni.2019.03.005

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.