Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8(+) T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness - Aix-Marseille Université Access content directly
Journal Articles Immunity Year : 2019

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

Abstract

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 antiviralT-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.

Domains

Genetics

Dates and versions

hal-02461449 , version 1 (30-01-2020)

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Cite

Jingxia Wu, Sicong Ma, Roger Sandhoff, Yanan Ming, Agnes Hotz-Wagenblatt, et al.. Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8(+) T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness. Immunity, 2019, 50 (5), pp.1218+. ⟨10.1016/j.immuni.2019.03.005⟩. ⟨hal-02461449⟩

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