%0 Journal Article
%A Wu, Jingxia
%A Ma, Sicong
%A Sandhoff, Roger
%A Ming, Yanan
%A Hotz-Wagenblatt, Agnes
%A Timmerman, Vincent
%A Bonello-Palot, Nathalie
%A Schlotter-Weigel, Beate
%A Auer-Grumbach, Michaela
%A Seeman, Pavel
%A Löscher, Wolfgang N
%A Reindl, Markus
%A Weiss, Florian
%A Mah, Eric
%A Weisshaar, Nina
%A Madi, Alaa
%A Mohr, Kerstin
%A Schlimbach, Tilo
%A Velasco Cárdenas, Rubí M-H
%A Koeppel, Jonas
%A Grünschläger, Florian
%A Müller, Lisann
%A Baumeister, Maren
%A Brügger, Britta
%A Schmitt, Michael
%A Wabnitz, Guido
%A Samstag, Yvonne
%A Cui, Guoliang
%T Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.
%J Immunity
%V 50
%N 5
%@ 1074-7613
%C New York, NY
%I Elsevier
%M DKFZ-2019-01371
%P 1218 - 1231.e5
%D 2019
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30952607
%R 10.1016/j.immuni.2019.03.005
%U https://inrepo02.dkfz.de/record/143809