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

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Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.
Immunity ( IF 25.5 ) Pub Date : 2019-04-02 , DOI: 10.1016/j.immuni.2019.03.005
Jingxia Wu ₁ , Sicong Ma ₂ , Roger Sandhoff ₃ , Yanan Ming ₄ , Agnes Hotz-Wagenblatt ₅ , Vincent Timmerman ₆ , Nathalie Bonello-Palot ₇ , Beate Schlotter-Weigel ₈ , Michaela Auer-Grumbach ₉ , Pavel Seeman ₁₀ , Wolfgang N Löscher ₁₁ , Markus Reindl ₁₁ , Florian Weiss ₁₂ , Eric Mah ₁₃ , Nina Weisshaar ₁₄ , Alaa Madi ₁₄ , Kerstin Mohr ₁ , Tilo Schlimbach ₁ , Rubí M-H Velasco Cárdenas ₁ , Jonas Koeppel ₁ , Florian Grünschläger ₁ , Lisann Müller ₁ , Maren Baumeister ₁ , Britta Brügger ₁₅ , Michael Schmitt ₁₆ , Guido Wabnitz ₁₇ , Yvonne Samstag ₁₇ , Guoliang Cui ₁₄

Affiliation

T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.
Lipid Pathobiochemistry Group (G131), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Internal Medicine IV, University Heidelberg Hospital, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
Core Facility Omics IT and Data Management, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Peripheral Neuropathy Research Group, Department of Biomedical Sciences, Institute Born Bunge, B-2610, University of Antwerp, Antwerpen, Belgium.
Department of Medical Genetics, Children Timone Hospital, 264 Rue Saint Pierre & Aix Marseille University, INSERM, MMG, U1251, 13385 Marseille, France.
Friedrich-Baur-Institut, Neurologische Klinik and Poliklinik Ludwig-Maximilians-Universität, 80336 München, Germany.
Department of Orthopaedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.
DNA Laboratory, Department of Child Neurology, 2nd Medical School, University Hospital Motol, Charles University, Prague, Czech Republic.
Clinical Department of Neurology, Medical University Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
Department of Psychiatry and Psychotherapy, University Hospital of Psychiatry, Bolligenstrasse 111, 3000 Bern, Germany.
School of Medicine, UC San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany.
Internal Medicine V, University Heidelberg Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Section Molecular Immunology, Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.

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.

中文翻译：

神经疾病HSAN-1相关基因SPTLC2的丧失可通过抑制T细胞代谢适应性来削弱CD8 + T细胞对感染的反应。

神经系统疾病HSAN-I的患者经常感染，这归因于缺乏疼痛感和无法为轻伤寻求护理。HSAN-I患者中保护性CD8 + T细胞是否受到影响尚不清楚。在这里，我们报道丝氨酸棕榈酰转移酶亚基SPTLC2的HSAN I相关突变抑制了人类T细胞反应。抗原刺激和炎症诱导SPTLC2表达，Sptlc2的小鼠T细胞特异性消融损害了抗病毒T细胞的扩增和效应子功能。Sptlc2缺乏症降低了鞘脂的生物合成通量，并导致雷帕霉素复合物1（mTORC1）的机械靶标，内质网（ER）应激和CD8 + T细胞死亡的激活时间延长。通过补充鞘脂并药理抑制ER应激诱导的细胞死亡，可以恢复HSAN-1患者PBMC和Sptlc2缺陷型小鼠中的保护性CD8 + T细胞应答。因此，SPTLC2通过将细胞外刺激转化为细胞内合成代谢信号来增强保护性免疫，并拮抗内质网应激，从而促进T细胞代谢适应性。

更新日期：2019-04-02

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