Journal Article

DKFZ-2019-01371

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Wu, J. (First author)DKFZ* ; Ma, S. (First author)DKFZ* ; Sandhoff, R. (First author)DKFZ* ; Ming, Y. ; Hotz-Wagenblatt, A.DKFZ* ; Timmerman, V. ; Bonello-Palot, N. ; Schlotter-Weigel, B. ; Auer-Grumbach, M. ; Seeman, P. ; Löscher, W. N. ; Reindl, M. ; Weiss, F. ; Mah, E. ; Weisshaar, N.DKFZ* ; Madi, A.DKFZ* ; Mohr, K.DKFZ* ; Schlimbach, T.DKFZ* ; Velasco Cárdenas, R. M.DKFZ* ; Koeppel, J.DKFZ* ; Grünschläger, F.DKFZ* ; Müller, L.DKFZ* ; Baumeister, M.DKFZ* ; Brügger, B. ; Schmitt, M. ; Wabnitz, G. ; Samstag, Y. ; Cui, G. (Last author)DKFZ*

2019
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.immuni.2019.03.005

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 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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Contributing Institute(s):

1. T-Zell-Metabolismus (D140)
2. T-Zell-Metabolismus (D192)
3. Lipid-Pathobiochemie (A411)
4. AG Lipid-Pathobiochemie (G131)

Research Program(s):

1. 314 - Tumor immunology (POF3-314) (POF3-314)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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