Diacylglycerol kinase zeta dictates CD40-mediated immune synapse formation, mTORC1 signaling and plasma cell fate in B lymphocytes
Fernandez-Barrecheguren, A.; Fernandez-Rego, A.; Fuentes-Cantos, L.; Pons, T.; Estrada, B. S.; Iborra-Pernichi, M.; Ebrahimi, T.; Sagrera-Aparisi, A.; Cogliati, S.; Martinez-Martin, N.; Jimenez-Saiz, R.; Carrasco, Y. R.
Show 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-{zeta} (DGK{zeta}) has a crucial role in activating the mTORC1 pathway and remodeling mitochondria downstream of CD40 signaling in B cells. DGK{zeta} governs organelle translocation to the CD40-mediated immune synapse and the recruitment of mTORC1 to lysosomes. DGK{zeta}-/- 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 DGK{zeta} as a key mediator of CD40 functions in the B cell response.
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