Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation
Brian T. Gaudette, … , Ivan Maillard, David Allman
Brian T. Gaudette, … , Ivan Maillard, David Allman
Published September 2, 2021
Citation Information: J Clin Invest. 2021;131(20):e151975. https://doi.org/10.1172/JCI151975.
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Research Article Immunology

Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation

Abstract

Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naive B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell-cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundance for numerous mTORC1- and Myc-regulated genes. Myc loss compromised plasma cell differentiation for MZ B cells, and reciprocally induced ectopic mTORC1 signaling in follicular B cells enabled division-independent differentiation and plasma cell–affiliated gene expression. We conclude that ongoing in situ Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state that enables rapid division-independent plasma cell differentiation.

Authors

Brian T. Gaudette, Carly J. Roman, Trini A. Ochoa, Daniela Gómez Atria, Derek D. Jones, Christian W. Siebel, Ivan Maillard, David Allman

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Figure 4

Induction of a plasma cell transcriptome despite cell-cycle arrest.

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Induction of a plasma cell transcriptome despite cell-cycle arrest. RNAs...
RNAseq was performed on cells sorted as in Supplemental Figure 4. Division-inhibited cells were sorted from undiluted CTV gate. (A) Expression of UPR hallmark genes previously shown to be upregulated in follicular (FO) B cells treated with an activation stimulus only (CpG) (top) versus those upregulated only in follicular B cells given a plasma cell inductive stimulus (CpG plus IL-4/5) (bottom) shown as a heat map by Z score across each row (22). (B) GSEA for the Protein Secretion Hallmark gene-set (left) and B220– BM plasma cell signature versus follicular B cells (right) as defined by the top 250 genes upregulated in B220– BM plasma cells versus follicular B cells (22) in MZ B cells stimulated with CpG plus IL-4/5 compared with freshly isolated cells with and without cell-cycle inhibition by PD0332991 or rapamycin is shown. NES: Normalized Enrichment Score; Nom.p.val: Nominal P value; and FDR.q.val: FDR q value. FDR-q computed using 1000 gene-set permutations. (C) Log2 TPM for the indicated genes is shown as the mean (line), 75% CI (box) and 95% CI (whisker) together with individual data points (jitter). All RNAseq data shown are prepared from 4 to 5 animal replicates.