Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness
| العنوان: | Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness |
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| المؤلفون: | Sicong Ma, Jonas Koeppel, Tilo Schlimbach, Florian Grünschläger, Kerstin Mohr, Beate Schlotter-Weigel, Alaa Madi, Roger Sandhoff, Jingxia Wu, Pavel Seeman, Rubí M.-H. Velasco Cárdenas, Florian Weiss, Eric Mah, Yvonne Samstag, Guido H. Wabnitz, Nathalie Bonello-Palot, Michaela Auer-Grumbach, Agnes Hotz-Wagenblatt, Maren Baumeister, Wolfgang Löscher, Yanan Ming, Guoliang Cui, Markus Reindl, Britta Brügger, Nina Weisshaar, Vincent Timmerman, Michael Schmitt, Lisann Müller |
| المساهمون: | German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Biomedical Sciences [Antwerp, Belgium] (Peripheral Neuropathy Research Group), University of Antwerp (UA), Institute Born-Bunge [Antwerp, Belgium], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Department of Neurology [Innsbruck, Austria], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Vesicular Transport, Biochemistry Center Heidelberg (BZH), Innsbruck Medical University [Austria] (IMU) |
| المصدر: | Immunity Immunity, 2019, 50 (5), pp.1218+. ⟨10.1016/j.immuni.2019.03.005⟩ Immunity, Elsevier, 2019, 50 (5), pp.1218+. ⟨10.1016/j.immuni.2019.03.005⟩ |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, [SDV.GEN]Life Sciences [q-bio]/Genetics, T cell, Immunology, Serine C-palmitoyltransferase, Inflammation, mTORC1, Biology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Unfolded protein response, Immunology and Allergy, Cytotoxic T cell, Human medicine, medicine.symptom, CD8, Intracellular |
| الوصف: | 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. |
| تدمد: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2019.03.005 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cbd2fc39c9fc8a1bca4885758e3856a2 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....cbd2fc39c9fc8a1bca4885758e3856a2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10747613 |
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| DOI: | 10.1016/j.immuni.2019.03.005 |