Decoding Germinal Center B Cell Dynamics: Acetyl-CoA driven Metabolic and Epigenetic Regulation of CD40-Dependent Responses

B lymphocytes are central mediators of humoral immunity, directing antibody production and immune memory thanks to tightly regulated differentiation programs. Cell maturation occurs through extensive metabolic and epigenetic reprogramming primarily at germinal centers (GCs), transient histological sites where B cell fate is determined. Here, I examined the role of acetyl-CoA, a key metabolite and substrate for histone acetylation, in regulating GC B cell fate downstream of CD40 signalling. In murine and human systems, CD40 stimulation enhanced phosphorylation of ATP-citrate lyase (ACLY), increasing acetyl-CoA levels and histone acetylation. I then performed isotope tracing to reveal the anabolic sources responsible for acetyl-CoA elevation: I found that lactate significantly contributes to the acetyl-CoA pool, fuelling histone acetylation. Genome-wide profiling (CUT&tag) showed that lactate-driven H3K27 acetylation activates Cbl signalling, which coordinates B cell proliferation and terminal differentiation within GCs. In line, lactate supplementation promoted S-phase entry of stimulated B cells, while pharmacological blockade of lactate uptake suppressed histone hyper-acetylation and cell proliferation. Diffuse large B cell lymphomas (DLBCLs) are the most common and aggressive form of non-Hodgkin lymphoma. Notably, only the GC–derived subtype of DLBCL exhibited elevated ACLY expression and heightened sensitivity to its targeting. These findings identify acetyl-CoA dependent histone acetylation as a metabolic-epigenetic axis directly controlled by CD40 signaling. As lactate within GCs is largely produced by glycolytic T cells, my data indicate a previously unrecognized metabolic intertwine between B and T lymphocytes. My work has ramifications for immunity, vaccination, and lymphomagenesis.