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.

Clinical Department of Neurology Medical University Innsbruck Anichstr 35 6020 Innsbruck Austria

Core Facility Omics IT and Data Management German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

Department of Medical Genetics Children Timone Hospital 264 Rue Saint Pierre and Aix Marseille University INSERM MMG U1251 13385 Marseille France

Department of Orthopaedics and Trauma Surgery Medical University of Vienna Vienna Austria

Department of Psychiatry and Psychotherapy University Hospital of Psychiatry Bolligenstrasse 111 3000 Bern Germany

DNA Laboratory Department of Child Neurology 2nd Medical School University Hospital Motol Charles University Prague Czech Republic

Faculty of Biosciences Heidelberg University 69120 Heidelberg Germany

Friedrich Baur Institut Neurologische Klinik and Poliklinik Ludwig Maximilians Universität 80336 München Germany

Heidelberg University Biochemistry Center Im Neuenheimer Feld 328 Heidelberg Germany

Internal Medicine 4 University Heidelberg Hospital Im Neuenheimer Feld 345 69120 Heidelberg Germany

Internal Medicine 5 University Heidelberg Hospital Im Neuenheimer Feld 410 69120 Heidelberg Germany

Lipid Pathobiochemistry Group Im Neuenheimer Feld 280 69120 Heidelberg Germany

Medical Faculty Heidelberg Heidelberg University 69120 Heidelberg Germany

Peripheral Neuropathy Research Group Department of Biomedical Sciences Institute Born Bunge B 2610 University of Antwerp Antwerpen Belgium

School of Medicine UC San Diego 9500 Gilman Drive La Jolla CA 92093 USA

Section Molecular Immunology Institute of Immunology Heidelberg University Im Neuenheimer Feld 305 69120 Heidelberg Germany

T Cell Metabolism Group Im Neuenheimer Feld 280 69120 Heidelberg Germany

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