Asparagine availability controls germinal center B cell homeostasis.

Autor: Yazicioglu YF; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Marin E; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Andrew HF; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Bentkowska K; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.; Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Johnstone JC; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Mitchell R; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Wong ZY; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Zec K; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Fergusson J; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Borsa M; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Raza IGA; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Attar M; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Ali M; Nuffield Department of Medicine Centre for Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand., Kronsteiner B; Nuffield Department of Medicine Centre for Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand., Furlani IL; Metabolomics STP, Francis Crick Institute, London NW1 1AT, UK., MacRae JI; Metabolomics STP, Francis Crick Institute, London NW1 1AT, UK., Devine MJ; Mitochondrial Neurobiology Laboratory, Francis Crick Institute, London NW1 1AT, UK; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Coles M; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Buckley CD; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Dunachie SJ; Nuffield Department of Medicine Centre for Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.; National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Clarke AJ; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Jazyk: angličtina
Zdroj: Science immunology [Sci Immunol] 2024 Dec 13; Vol. 9 (102), pp. eadl4613. Date of Electronic Publication: 2024 Dec 13.
DOI: 10.1126/sciimmunol.adl4613
Abstrakt: The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
Databáze: MEDLINE