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

Wu, Jingxia; Ma, Sicong; Sandhoff, Roger; Ming, Yanan; Hotz-Wagenblatt, Agnes; Timmerman, Vincent; Bonello-Palot, Nathalie; Schlotter-Weigel, Beate; Auer-Grumbach, Michaela; Seeman, Pavel; Löscher, Wolfgang N.; Reindl, Markus; Weiss, Florian; Mah, Eric; Weisshaar, Nina; Madi, Alaa; Mohr, Kerstin; Schlimbach, Tilo; Cardenas, Rubi M.-H. Velasco; Koeppel, Jonas; Grünschlaeger, Florian; Müller, Lisann; Baumeister, Maren; Bruegger, Britta; Schmitt, Michael; Wabnitz, Guido; Samstag, Yvonne und Cui, Guoliang (2019): Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8(+) T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness. In: Immunity, Bd. 50, Nr. 5

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 antiviralT-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1074-7613
• Sprache: Englisch