TY  - JOUR
AU  - Wu, Jingxia
AU  - Ma, Sicong
AU  - Sandhoff, Roger
AU  - Ming, Yanan
AU  - Hotz-Wagenblatt, Agnes
AU  - Timmerman, Vincent
AU  - Bonello-Palot, Nathalie
AU  - Schlotter-Weigel, Beate
AU  - Auer-Grumbach, Michaela
AU  - Seeman, Pavel
AU  - Löscher, Wolfgang N
AU  - Reindl, Markus
AU  - Weiss, Florian
AU  - Mah, Eric
AU  - Weisshaar, Nina
AU  - Madi, Alaa
AU  - Mohr, Kerstin
AU  - Schlimbach, Tilo
AU  - Velasco Cárdenas, Rubí M-H
AU  - Koeppel, Jonas
AU  - Grünschläger, Florian
AU  - Müller, Lisann
AU  - Baumeister, Maren
AU  - Brügger, Britta
AU  - Schmitt, Michael
AU  - Wabnitz, Guido
AU  - Samstag, Yvonne
AU  - Cui, Guoliang
TI  - Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.
JO  - Immunity
VL  - 50
IS  - 5
SN  - 1074-7613
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2019-01371
SP  - 1218 - 1231.e5
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30952607
DO  - DOI:10.1016/j.immuni.2019.03.005
UR  - https://inrepo02.dkfz.de/record/143809
ER  -