Abstract
To mount a robust T-dependent immune response, antigen-specific B lymphocytes require CD40 stimulation through immune synapse formation with CD4⁺ T follicular helper cells. CD40 triggers the activation of mTORC1 and remodels the mitochondria to meet increased bioenergetic and anabolic demands. We found that diacylglycerol-kinase-ζ (DGKζ) supports mTORC1 activation downstream CD40 signalling in B cells. Mechanistically, DGKζ governs organelle translocation to the CD40-mediated immune synapse and the recruitment of mTORC1 to lysosomes, needed for its activation and function. The production of phosphatidic acid by DGKζ is crucial for these processes. DGKζ^-/- B cells exhibit defects in protein biosynthesis, metabolite transporters expression and cell cycle progression, together with a dysregulation in the transcriptional network that determines B cell fate. To sustain the bioenergetic and metabolic demands, DGKζ^-/- B cells enhance mitochondrial function. These defects lead to an impaired germinal centre response and a reduced generation of long-lived compartments of plasma cells and memory cells in vivo. Overall, our data identify DGKζ as an essential mediator of CD40 functions in the B cell immune response.