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

Immunity. 2019 May 21;50(5):1218-1231.e5. doi: 10.1016/j.immuni.2019.03.005. Epub 2019 Apr 2.

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 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.

Keywords: CD8+ T cells; ER stress; HSAN-I; SPTLC2; neurological diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / immunology
  • Female
  • Hereditary Sensory and Autonomic Neuropathies / genetics*
  • Humans
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Serine C-Palmitoyltransferase / genetics*
  • Signal Transduction / immunology
  • Sphingolipids / biosynthesis

Substances

  • Cytokines
  • Sphingolipids
  • SPTLC2 protein, human
  • Serine C-Palmitoyltransferase
  • Mechanistic Target of Rapamycin Complex 1