Diacylglycerol kinase ζ dictates CD40-mediated immune synapse formation, mTORC1 signaling and plasma cell fate in B lymphocytes

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 mammalian target of rapamycin complex-1 (mTORC1) and remodels the mitochondria to meet increased bioenergetic and anabolic demands. We show that diacylglycerol-kinase-ζ (DGKζ) has a crucial role in activating the mTORC1 pathway and remodeling mitochondria downstream of CD40 signaling in B cells. DGKζ governs organelle translocation to the CD40-mediated immune synapse and the recruitment of mTORC1 to lysosomes. DGKζ−/− B cells exhibited impaired mitochondria function, protein biosynthesis, metabolite transporter expression and cell cycle progression, accompanied by dysregulation of the transcriptional network governing B cell fate. These defects lead to a blockage in the progression of the germinal center response and plasma cell differentiation in vivo. Our findings establish DGKζ as a key mediator of CD40 functions in the B cell response. Competing Interest Statement The authors have declared no competing interest.