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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

ABSTRACT: Hereditary sensory and autonomic neuropathy type I (HSAN-I) is neurological disorder characterized by distal sensory neuron dysfunction, frequent infections, and ulcerative mutilations. It remains unknown if HSAN-I directly dampens protective immunity. Here we report that HSAN-I-causing mutations of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) affect human T cell responses. T cell antigenic stimulation and inflammation induce SPTLC2 expression. Murine T cell-specific ablation of Sptlc2 fundamentally impairs antiviral T cell survival and effector function. Mechanistically, SPTLC2-deficiency reduces sphingolipid biosynthetic flux and causes a prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress and CD8+ T cell death. Antiviral CD8+ T cell responses are restored by supplementing sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Our study reveals that SPTLC2 underpins protective adaptive immunity by translating extracellular stimuli into intracellular anabolic signals and reducing cellular stress to maintain metabolic reprogramming sustainability

ORGANISM(S): Mus musculus

PROVIDER: GSE112715 | GEO | 2019/04/02

REPOSITORIES: GEO

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Project description:During a T cell response, naÃ¯ve CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells (MPECs) further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. Here, we report that the transcription factor FoxO1 plays an integral role in facilitating effector to memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of scenescence and progressive attrition in polyfunctionality, which in turn led to impared recall responses and poor protective immunity. These data suggest that FoxO1 is essential for active maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow Single-cell suspensions from splenocytes of eight samples WT (control) and FoxO1-/- (experimental) LCMV-immune mice were prepared using standard procedures. CD8 T cells were then isoloated using Thy1.2 (CD90.2) (30-H12) microbeads (Miltenyi Biotec). Cells were then stained with anti-CD8, anti-CD44 and Db/NP396 MHC class I tetramer. Activated (CD8+CD44hi), naive (CD8+CD44lo), and virus-specific CD8 T cells were sorted using FACSAria II instrument (BD Biosciences). The purity of the cells was >95%. Total RNA was extracted from the sorted cells by Trizol Reagent. RNA samples were reverse transcribed and Cy3-labeled cDNAs were hyrbidized to Agilent whole Mouse Genome Oligo Microarrays. Fluorscence signals were detected using Agilent's Microarray Scanner system, data was analyzed using the Rosetta Resolver gene expression data analysis system and genes with a fold change < and p-values <0.01 were identified. Microarray data discussed in the paper is focused on virus-specific memory CD8 T cells from samples WT_Tet_2 vs KO_Tet_2.

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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

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