Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is neurological disorder characterized by distal sensory neuron dysfunction, frequent infections, and ulcerative mutilations. It remains unknown if HSAN-I directly dampens protective immunity. Here we report that HSAN-I-causing mutations of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) affect human T cell responses. T cell antigenic stimulation and inflammation induce SPTLC2 expression. Murine T cell-specific ablation of Sptlc2 fundamentally impairs antiviral T cell survival and effector function. Mechanistically, SPTLC2-deficiency reduces sphingolipid biosynthetic flux and causes a prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress and CD8+ T cell death. Antiviral CD8+ T cell responses are restored by supplementing sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Our study reveals that SPTLC2 underpins protective adaptive immunity by translating extracellular stimuli into intracellular anabolic signals and reducing cellular stress to maintain metabolic reprogramming sustainability Overall design: Triplicates of each group were used for RNA-seq. Four groups were studied: Wild-type and SPTLC2-deficient CD8+ T cells, harvested from either naïve mice (D0) or mice infected with LCMV Armstrong 8 days earlier (D8).

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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