Diacylglycerol kinase ζ in B lymphocytes supports...

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

Abstract

To mount a robust T cell–dependent immune response, antigen-specific B lymphocytes require the stimulation of the transmembrane receptor CD40 through immune synapse formation with CD4 + T follicular helper cells. CD40 stimulates the activation of mammalian target of rapamycin complex 1 (mTORC1) and remodels mitochondria to meet the increased bioenergetic and anabolic demands of activated B cells. Here, we found that diacylglycerol kinase ζ (DGKζ) supported mTORC1 activation downstream of CD40 stimulation in mouse B cells. We showed that DGKζ was required for organellar translocation to the CD40-mediated immune synapse and for the recruitment of mTORC1 to lysosomes, the latter of which was necessary for mTORC1 activation and function. The production of phosphatidic acid by DGKζ was crucial for these processes. DGKζ −/− B cells exhibited defects in protein biosynthesis, metabolite transporter expression, and cell cycle progression, together with dysregulation of the transcriptional network that determines B cell fate. To sustain their bioenergetic and metabolic demands, DGKζ −/− B cells enhanced their mitochondrial function. Together, these effects of DGKζ loss led to decreases in germinal center responses and in the generation of long-lived plasma cells and memory B cells in mice. Thus, our data identify DGKζ as an essential mediator of CD40 functions in the B cell immune response.

Authors

Fernández-Barrecheguren A; Fernández-Rego A; Fuentes-Cantos L; Pons T; Estrada BS; Iborra-Pernichi M; de la Esperanza MV; Ebrahimi T; Sagrega-Aparisi A; Cogliati S