PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes
EntityUAM. Departamento de Biología Molecular
PublisherB M J Group
10.1186/s40425-019-0628-7Journal for ImmunoTherapy of Cancer 7.1 (2019): 151
Funded byThis work was funded by grants from the Spanish Ministerio de Economía y Competitividad (MINECO) (SAF2014–54475-R and SAF2017–83732-R to SM; SAF2016–75916-R to JMC; AEI/FEDER, EU), the Instituto de Salud Carlos III (PT17 PT17/0009/0019, AEI/FEDER, EU), the Comunidad de Madrid (B2017/ BMD-3733; Inmunothercan-CM, to SM), and the Merck-Salud Foundation (to SM). JO, JS and CN-T are supported by predoctoral fellowships from the MINECO and the EU European Social Fund
ProjectGobierno de España. SAF2014–54475-R; Gobierno de España. SAF2017–83732-R; Gobierno de España. SAF2016–75916-R; Comunidad de Madrid. B2017/BMD-3733/Inmunothercan-CM
SubjectsCD8; Cristae; Metabolism; MICOS; Mitochondrion; PD-1; RNA-seq; Biología y Biomedicina / Biología
Rights© 2019 The Author(s)
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
Background: Binding of the programmed death-1 (PD-1) receptor to its ligands (PD-L1/2) transduces inhibitory signals that promote exhaustion of activated T cells. Blockade of the PD-1 pathway is widely used for cancer treatment, yet the inhibitory signals transduced by PD-1 in T cells remain elusive. Methods: Expression profiles of human CD8+ T cells in resting, activated (CD3 + CD28) and PD-1-stimulated cells (CD3 + CD28 + PD-L1-Fc) conditions were evaluated by RNA-seq. Bioinformatic analyses were used to identify signaling pathways differentially regulated in PD-1-stimulated cells. Metabolic analyses were performed with SeaHorse technology, and mitochondrial ultrastructure was determined by transmission electron microscopy. PD-1-regulated mitochondrial genes were silenced using short-hairpin RNA in primary cells. Blue native gel electrophoresis was used to determine respiratory supercomplex assembly. Results: PD-1 engagement in human CD8+ T cells triggers a specific, progressive genetic program different from that found in resting cells. Gene ontology identified metabolic processes, including glycolysis and oxidative phosphorylation (OXPHOS), as the main pathways targeted by PD-1. We observed severe functional and structural alterations in the mitochondria of PD-1-stimulated cells, including a reduction in the number and length of mitochondrial cristae. These cristae alterations were associated with reduced expression of CHCHD3 and CHCHD10, two proteins that form part of the mitochondrial contact site and cristae organizing system (MICOS). Although PD-1-stimulated cells showed severe cristae alterations, assembly of respiratory supercomplexes was unexpectedly greater in these cells than in activated T cells. CHCHD3 silencing in primary CD8+ T cells recapitulated some effects induced by PD-1 stimulation, including reduced mitochondrial polarization and interferon-γproduction following T cell activation with anti-CD3 and-CD28 activating antibodies. Conclusions: Our results suggest that mitochondria are the main targets of PD-1 inhibitory activity. PD-1 reprograms CD8+ T cell metabolism for efficient use of fatty acid oxidation; this mitochondrial phenotype might explain the long-lived phenotype of PD-1-engaged T cells
Google Scholar:Ogando, Jesús - Saéz, Mariá Eugenia - Santos, Javier - Nuevo-Tapioles, Cristina - Gut, Marta - Esteve-Codina, Anna - Heath, Simon - González-Pérez, Antonio - Cuezva Marcos, José Manuel - Lacalle, Rosa Ana - Mañes, Santos
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