BAFF antagonism via the BAFF receptor 3 binding site attenuates BAFF 60-mer-induced classical NF-κB signaling and metabolic reprogramming of B cells

Elsevier

Available online 9 September 2022, 104603

Cellular ImmunologyHighlights•

BAFF 3-mer, BAFF 60-mer, and higher order multimers are present in human plasma.

Compared to the BAFF 3-mer, BAFF 60-mer strongly induces the transcriptome of B cells.

BAFF 60-mer is critical for classical NF-κB signaling and glucose oxidation.

BAFF 60-mer-induced classical NF-κB signaling drives glucose oxidation.

BR3 binding site on BAFF is critical BAFF 60-mer-induced B cell hyperactivation.

Abstract

Human recombinant B cell activating factor (BAFF) is secreted as 3-mers, which can associate to form 60-mers in culture supernatants. However, the presence of BAFF multimers in humans is still debated and it is incompletely understood how BAFF multimers activate the B cells. Here, we demonstrate that BAFF can exist as 60-mers or higher order multimers in human plasma. In vitro, BAFF 60-mer strongly induced the transcriptome of B cells which was partly attenuated by antagonism using a soluble fragment of BAFF receptor 3. Furthermore, compared to BAFF 3-mer, BAFF 60-mer strongly induced a transient classical and prolonged alternate NF-κB signaling, glucose oxidation by both aerobic glycolysis and oxidative phosphorylation, and succinate utilization by mitochondria. BAFF antagonism selectively attenuated classical NF-κB signaling and glucose oxidation. Altogether, our results suggest critical roles of BAFF 60-mer and its BAFF receptor 3 binding site in hyperactivation of B cells.

Keywords

BAFF multimers

B cell activation

Transcriptomics

NF-κB signaling

Metabolic reprogramming

AbbreviationsBAFF

B cell activating Factor

BR3

BAFF receptor 3, BAFF-R

TACI

Transmembrane activator and CAML interactor

BCMA

B-cell maturation antigen

mBaffR-Fc

Murine BR3 ecto-domain fused to murine IgG1 Fc fragment, blocks BR3 binding site on BAFF

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

IKKα

Inhibitor of NF-κB kinase α

IKKβ

Inhibitor of NF-κB kinase β

SEC

Size exclusion chromatography

FPKM

Fragments Per Kilobase of transcript sequence per Millions base pairs sequenced

IPA

Ingenuity Pathway Analysis

OXPHOS

Oxidative phosphorylation

OCR

Oxygen consumption rate

ECAR

Extracellular acidification rate

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© 2022 Published by Elsevier Inc.

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