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Acid ceramidase regulates CD8+ T-cell exhaustion via type I interferon-mediated upregulation of PD-L1
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Acid ceramidase regulates CD8+ T-cell exhaustion via type I interferon-mediated upregulation of PD-L1
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Acid ceramidase regulates CD8+ T-cell exhaustion via type I interferon-mediated upregulation of PD-L1
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Journal Article
Acid ceramidase regulates CD8+ T-cell exhaustion via type I interferon-mediated upregulation of PD-L1
2025
Overview
Besides its robust antiviral activity, type I interferon (IFN-I) also exerts immunomodulatory effects and can even drive pathology during chronic viral infections. Mechanisms that regulate IFN-I induction during virus infection, thus strongly affecting the outcome of disease, remain to be defined. Here, using the lymphocytic choriomeningitis virus (LCMV) Docile strain, we identified acid ceramidase (aCDase,
) as a critical lipid-metabolic regulator of endosomal, nucleic acid-driven IFN-I responses and disease outcome during chronic virus infection. aCDase is highly expressed in plasmacytoid dendritic cells (pDCs) and required for robust early IFN-I production. aCDase deficiency resulted in ceramide accumulation, blunting IFN-α/β induction, impairing IFN-I-dependent upregulation of programmed death-ligand 1 (PD-L1) on antigen-presenting cells and preventing the exhaustion of virus-specific CD8
T cells, leading to severe immunopathology. This pathology is abrogated by CD8
T-cell depletion or by adoptive transfer of IFN-I-induced PD-L1-expressing macrophages. Conversely, limiting ceramide production in acid sphingomyelinase (Asm)-deficient mice prevented ceramide accumulation, and pDCs showed accelerated IFN-I induction. Mechanistically, ceramide abundance regulated IFN-I production by altering endosomal signaling microdomains. Collectively, our findings reveal ceramide homeostasis as a key determinant of IFN-I-driven CD8
T-cell exhaustion and immunopathology during chronic viral infection and highlight aCDase as a potential therapeutic target.
Publisher
Frontiers Media SA,Frontiers Media S.A
Subject
/ Acid Ceramidase - immunology
/ Acid Ceramidase - metabolism
/ Animals
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - metabolism
/ Ceramide
/ Dendritic Cells - immunology
/ Dendritic Cells - metabolism
/ Interferon Type I - immunology
/ Interferon Type I - metabolism
/ Kinases
/ Ligands
/ Lipids
/ Lymphocytic Choriomeningitis - immunology
/ Lymphocytic choriomeningitis virus - immunology
/ Mice
/ programmed death ligand 1 (PD-L1)
/ Proteins
/ Sensors
/ Sphingomyelin phosphodiesterase
/ Viruses
