Germinal centre (GC) B cells proliferate at some of the highest rates of any mammalian cell, yet the metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling of GC B cells, and found that metabolism of the non-essential amino acid asparagine (Asn) was highly upregulated. Asn was conditionally essential to B cells, and its synthetic enzyme, asparagine synthetase (ASNS) was markedly upregulated following their activation, through the integrated stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted, GC formation, and B cell survival in low Asn conditions were severely impaired, and removal of environmental Asn by asparaginase or dietary restriction markedly compromised the GC reaction. Using stable isotope tracing, we found that metabolic adaptation to the absence of Asn requires ASNS, and that oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides was particularly sensitive to Asn deprivation. Altogether, we reveal that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.

Asparagine availability controls B cell homeostasis