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.
- MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- cytokiny biosyntéza MeSH
- dědičné senzorické a autonomní neuropatie genetika MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfocytární choriomeningitida imunologie virologie MeSH
- mechanistické cílové místo rapamycinového komplexu 1 metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- proliferace buněk MeSH
- serin-C-palmitoyltransferasa genetika MeSH
- sfingolipidy biosyntéza MeSH
- signální transdukce imunologie MeSH
- stres endoplazmatického retikula genetika imunologie MeSH
- virus lymfocytární choriomeningitidy imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
