Loss of neurological disease HSAN-I-associated gene SPTLC2 impairs CD8+ T cell responses to infection by inhibiting T cell metabolic fitness
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 p...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2 April 2019
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| In: |
Immunity
Year: 2019, Jahrgang: 50, Heft: 5, Pages: 1218-1231.e5 |
| ISSN: | 1097-4180 |
| DOI: | 10.1016/j.immuni.2019.03.005 |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.1016/j.immuni.2019.03.005 Verlag: http://www.sciencedirect.com/science/article/pii/S1074761319300950 
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| Verfasserangaben: | Jingxia Wu, Sicong Ma, Roger Sandhoff, Yanan Ming, Agnes Hotz-Wagenblatt, Vincent Timmerman, Nathalie Bonello-Palot, Beate Schlotter-Weigel, Michaela Auer-Grumbach, Pavel Seeman, Wolfgang N. Löscher, Markus Reindl, Florian Weiss, Eric Mah, Nina Weisshaar, Alaa Madi, Kerstin Mohr, Tilo Schlimbach, Rubí M. -H. Velasco Cárdenas, Jonas Koeppel, Florian Grünschläger, Lisann Müller, Maren Baumeister, Britta Brügger, Michael Schmitt, Guido Wabnitz, Yvonne Samstag, and Guoliang Cui |
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| 520 | |a 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. | ||
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