Asparagine availability controls germinal center B cell homeostasis
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 <i>Asns</i> 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.
Authors
- Izadora Liranço Furlani (ORCID: https://orcid.org/0000-0002-2745-7612)
- Zhi Yi Wong (ORCID: https://orcid.org/0000-0003-1452-1387)
- Kristina Zec (ORCID: https://orcid.org/0000-0003-1005-2368)
- Alexander J. Clarke (ORCID: https://orcid.org/0000-0003-2846-7860)
- Mark Coles (ORCID: https://orcid.org/0000-0001-8079-9358)
- Eros Marin
- Michael J. Devine (ORCID: https://orcid.org/0000-0001-6076-3382)
- Christopher Dominic Buckley (ORCID: https://orcid.org/0000-0001-6924-6402)
- Moustafa Attar (ORCID: https://orcid.org/0000-0003-4116-1276)
- Iwan G. A. Raza (ORCID: https://orcid.org/0000-0002-1724-1703)
- Yavuz F. Yazicioglu (ORCID: https://orcid.org/0000-0003-3731-9333)
- Robert J. Mitchell (ORCID: https://orcid.org/0000-0002-9608-5381)
- Barbara Kronsteiner (ORCID: https://orcid.org/0000-0003-0867-2867)
- Susanna Dunachie (ORCID: https://orcid.org/0000-0001-5665-6293)
- Joannah R. Fergusson (ORCID: https://orcid.org/0000-0001-9223-1209)
- James I. MacRae (ORCID: https://orcid.org/0000-0002-1464-8583)
- Mariana Borsa (ORCID: https://orcid.org/0000-0003-1519-2597)
- Mohammad Ali (ORCID: https://orcid.org/0000-0003-0170-7182)
- Julia C. Johnstone
- Hana F. Andrew
- Karolina Bentkowska
Institutions
- Mahidol University (TH)
- Angkor Hospital for Children (KH)
- The Francis Crick Institute (GB)
- Nuffield Orthopaedic Centre (GB)
- Oxford Health NHS Foundation Trust (GB)
- National Institute for Health and Care Research (GB)
- University of Oxford (GB)
- Nuffield Health (GB)
- Mahidol Oxford Tropical Medicine Research Unit (TH)
- Oxford University Hospitals NHS Trust (GB)
- University College London (GB)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1126/sciimmunol.adl4613
- Citations
- 10
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 2.40
Funders
- Wellcome Trust
- Francis Crick Institute
- Cancer Research UK
- National Institute for Health and Care Research
- University of Oxford
- Versus Arthritis
- Medical Research Council
- NIHR Oxford Biomedical Research Centre