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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

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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Main Authors: Wu, Jingxia (Author) , Ma, Sicong (Author) , Sandhoff, Roger (Author) , Ming, Yanan (Author) , Hotz-Wagenblatt, Agnes (Author) , Weisshaar, Nina (Author) , Madi, Alaa (Author) , Mohr, Kerstin (Author) , Schlimbach, Tilo (Author) , Velasco Cárdenas, Rubí Misol-Há (Author) , Koeppel, Jonas (Author) , Grünschläger, Florian (Author) , Müller, Lisann (Author) , Baumeister, Maren (Author) , Brügger, Britta (Author) , Schmitt, Michael (Author) , Wabnitz, Guido H. (Author) , Samstag, Yvonne (Author) , Cui, Guoliang (Author)
Format: Article (Journal)
Language:English
Published: 2 April 2019
In: Immunity
Year: 2019, Volume: 50, Issue: 5, Pages: 1218-1231.e5
ISSN:1097-4180
DOI:10.1016/j.immuni.2019.03.005
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 18.12.2019
Physical Description:Online Resource
ISSN:1097-4180
DOI:10.1016/j.immuni.2019.03.005

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