Dataset Information

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

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.

SUBMITTER: Wu J

PROVIDER: S-EPMC6531359 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8<sup>+</sup> T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Wu Jingxia J Ma Sicong S Sandhoff Roger R Ming Yanan Y Hotz-Wagenblatt Agnes A Timmerman Vincent V Bonello-Palot Nathalie N Schlotter-Weigel Beate B Auer-Grumbach Michaela M Seeman Pavel P Löscher Wolfgang N WN Reindl Markus M Weiss Florian F Mah Eric E Weisshaar Nina N Madi Alaa A Mohr Kerstin K Schlimbach Tilo T Velasco Cárdenas Rubí M-H RM Koeppel Jonas J Grünschläger Florian F Müller Lisann L Baumeister Maren M Brügger Britta B Schmitt Michael M Wabnitz Guido G Samstag Yvonne Y Cui Guoliang G

Immunity 20190402 5

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<sup>+</sup> 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 an ...[more]

PMID: 30952607

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Project description:CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.

Dataset Information

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

Publications

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8<sup>+</sup> T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

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Dataset Information

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

Publications

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8&lt;sup&gt;+&lt;/sup&gt; T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8<sup>+</sup> T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.