Category: Immunodeficiency: primary or acquired
Human B cell maturation is organized through a series of highly controlled developmental checkpoints. After leaving the bone marrow, the BCR repertoire progressively contracts as the pool of transitional B cells undergoes selection and acquires a mature follicular B cell phenotype. The triggers controlling the final steps in B cell maturation are largely unknown in humans. Using bulk RNA-seq on FACS-sorted B cells, we identified a dramatic metabolic switch, orchestrated by mTORC1 downregulation, that takes place as B cells progress from the transitional to the follicular B cell stage. This reprogramming encompasses ribosome and protein biogenesis, as well as aerobic respiration. Reinforcing the fundamental role of the reduction of mTORC1 signaling in B cell maturation, CVID patients with gain-of-function PI3Kδ mutations, which cause increased tonic mTORC1 signaling, exhibit a profound loss of follicular B cells. The attenuation of mTORC1 activity in follicular B cells was associated with a coordinated upregulation of the ABCB1 transporter, promoting the accumulation of extracellular ATP, which is broken down to adenosine by the conjugated action of extracellular exonuclease, CD39 and CD73, fostering the activation of the mTORC1 inhibitor, AMPK. Taken as a whole, these data suggest that mTORC1 governs a novel checkpoint in the maturation of human B cells. To pass this checkpoint, developing B cells require the attenuation of mTORC1. Consequently, late transitional B cells limit mTORC1 signaling by activating AMPK through the adenosine salvage pathway.
Hugues Allard-Chamard– Post doctoral fellow, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Medicine, Harvard University, Cambridge, MA, USA | Division of Rheumatology, FMSS, Sherbrooke, Québec, Canada.
Jocelyn R. Farmer– Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Medicine, Harvard University, Cambridge, MA, USA |Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA