| First Author | Wu J | Year | 2019 |
| Journal | Immunity | Volume | 50 |
| Issue | 5 | Pages | 1218-1231.e5 |
| PubMed ID | 30952607 | Mgi Jnum | J:282529 |
| Mgi Id | MGI:6381179 | Doi | 10.1016/j.immuni.2019.03.005 |
| Citation | Wu J, et al. (2019) Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8(+) T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness. Immunity 50(5):1218-1231.e5 |
| abstractText | 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. |
