Metabolic crosstalk between c-Myc and glutamine utilization sustains IgM+ B-cell immunity in teleosts.

Abstract

B-cell responses rely on a tightly coordinated interplay between transcriptional programs and metabolic reprogramming. Upon activation, B cells remodel their metabolic profiles, with enhanced glutamine metabolism supporting biomass synthesis and proliferation. However, whether and how glutaminolysis underpins B-cell responses in early vertebrates remains largely unexplored. Here, using the Nile tilapia (Oreochromis niloticus) as a model, we demonstrate that IgM+ B cells markedly increase glutamine utilization upon activation. Glutamine deprivation impaired B-cell activation and proliferation, whereas glutamine supplementation promoted these processes. During Edwardsiella piscicida infection, pharmacological inhibition of glutamine metabolism significantly reduced the expansion of IgM+ B cells and compromised antibody secretion. Mechanistically, glutamine metabolism in tilapia IgM+ B cells was governed by the transcription factor c-Myc. Inhibition of c-Myc disrupted glutaminolysis, leading to diminished B-cell proliferation and antibody production. Upon activation, IgM+ B cells coordinated c-Myc expression and downstream glutamine metabolism through the mTORC1 and ERK signaling pathways, thereby coordinating metabolic and immune functions. Notably, this regulatory mechanism operated in a B cell-intrinsic manner and was independent of T-cell help. Collectively, our findings reveal that teleost B cells possess evolutionarily conserved and sophisticated immunometabolic regulatory programs. This study provides new insights into how metabolic pathways are integrated with immune signaling to control B-cell function, highlighting coordinated immunometabolic regulation as a fundamental mechanism underlying vertebrate B-cell immunity.