An evolutionarily conserved program of B-cell development and activation in zebrafish

Transforming growth factor β (TGFβ) can inhibit thein vitroproliferation, survival and differentiation of B cell progenitors, mature B lymphocytes and plasma cells. Here we demonstrate unexpected, age-dependent reductions in the bone marrow (BM) B cell progenitors and immature B cells in TGFβ1-/-mice. To evaluate TGFβ responsiveness during normal B lineage development, cells were cultured in interleukin 7 (IL7)±TGFβ. Picomolar doses of TGFβ1 reduced pro-B cell recoveries at every timepoint. By contrast, the pre-B cells were initially reduced in number, but subsequently increased compared to IL7 alone, resulting in a 4-fold increase in the growth rate for the pre-B cell population. Analysis of purified BM sub-populations indicated that pro-B cells and the earliest BP1-pre-B cells were sensitive to the inhibitory effects of TGFβ1. However, the large BP1+pre-B cells, although initially reduced, were increased in number at days 5 and 7 of culture. These results indicate that TGFβ1 is important for normal B cell developmentin vivo, and that B cell progenitors are differentially affected by the cytokine according to their stage of differentiation.

Download Full-text

Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

Journal of Experimental Medicine ◽

10.1084/jem.194.11.1583 ◽

2001 ◽

Vol 194 (11) ◽

pp. 1583-1596 ◽

Cited By ~ 112

Author(s):

Gregory Bannish ◽

Ezequiel M. Fuentes-Pananá ◽

John C. Cambier ◽

Warren S. Pear ◽

John G. Monroe

Keyword(s):

B Cells ◽

B Cell ◽

B Lymphocyte ◽

Antigen Receptor ◽

Cell Development ◽

B Cell Development ◽

B Lymphopoiesis ◽

Biologically Relevant ◽

Developmental Progression

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

Download Full-text

Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1602728113 ◽

2016 ◽

Vol 113 (32) ◽

pp. 9063-9068 ◽

Cited By ~ 26

Author(s):

Nilushi S. De Silva ◽

Michael M. Anderson ◽

Amanda Carette ◽

Kathryn Silva ◽

Nicole Heise ◽

...

Keyword(s):

Transcription Factors ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Plasma Cells ◽

Alternative Pathway ◽

Cell Development ◽

B Cell Development ◽

Cell Surface Receptor ◽

Signaling Cascade

The NF-κB signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-κB in these cells. The NF-κB signaling cascade is comprised of two branches, the canonical and alternative NF-κB pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-κB2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-κB2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/NF-κB2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-κB2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen-specific antibody-secreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-κB pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway.

Download Full-text

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

Blood ◽

10.1182/blood-2016-08-733469 ◽

2017 ◽

Vol 129 (19) ◽

pp. 2645-2656 ◽

Cited By ~ 42

Author(s):

Idoia García-Ramírez ◽

Saber Tadros ◽

Inés González-Herrero ◽

Alberto Martín-Lorenzo ◽

Guillermo Rodríguez-Hernández ◽

...

Keyword(s):

B Cell ◽

Cell Development ◽

B Cell Development ◽

Disease Etiology ◽

Key Points ◽

Epigenetic Signatures

Key Points Crebbp inactivation perturbs B-cell development, but cooperates with Bcl2 overexpression to promote lymphoma. Transcriptional and epigenetic signatures of Crebbp loss implicate Myc in disease etiology.

Download Full-text

IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF

Journal of Experimental Medicine ◽

10.1084/jem.20050158 ◽

2005 ◽

Vol 201 (8) ◽

pp. 1197-1203 ◽

Cited By ~ 154

Author(s):

Kazu Kikuchi ◽

Anne Y. Lai ◽

Chia-Lin Hsu ◽

Motonari Kondo

Keyword(s):

Transcription Factor ◽

B Cells ◽

B Cell ◽

Target Genes ◽

Cell Development ◽

B Cell Development ◽

Receptor Signaling ◽

Cell Stage ◽

Transcription Factor Network ◽

Stage Transition

Cytokine receptor signals have been suggested to stimulate cell differentiation during hemato/lymphopoiesis. Such action, however, has not been clearly demonstrated. Here, we show that adult B cell development in IL-7−/− and IL-7Rα2/− mice is arrested at the pre–pro-B cell stage due to insufficient expression of the B cell–specific transcription factor EBF and its target genes, which form a transcription factor network in determining B lineage specification. EBF expression is restored in IL-7−/− pre–pro-B cells upon IL-7 stimulation or in IL-7Rα−/− pre–pro-B cells by activation of STAT5, a major signaling molecule downstream of the IL-7R signaling pathway. Furthermore, enforced EBF expression partially rescues B cell development in IL-7Rα−/− mice. Thus, IL-7 receptor signaling is a participant in the formation of the transcription factor network during B lymphopoiesis by up-regulating EBF, allowing stage transition from the pre–pro-B to further maturational stages.

Download Full-text

Induction of metabolic quiescence defines the transitional to follicular B cell switch

Science Signaling ◽

10.1126/scisignal.aaw5573 ◽

2019 ◽

Vol 12 (604) ◽

pp. eaaw5573 ◽

Cited By ~ 3

Author(s):

Jocelyn R. Farmer ◽

Hugues Allard-Chamard ◽

Na Sun ◽

Maimuna Ahmad ◽

Alice Bertocchi ◽

...

Keyword(s):

B Cells ◽

Cell Surface ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Ampk Activation ◽

Cell Stage ◽

Extracellular Adenosine ◽

Transitional B Cells ◽

Follicular B Cells

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5′-monophosphate–activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

Download Full-text

CtIP is essential for early B cell proliferation and development in mice

Journal of Experimental Medicine ◽

10.1084/jem.20181139 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1648-1663 ◽

Cited By ~ 7

Author(s):

Xiangyu Liu ◽

Xiaobin S. Wang ◽

Brian J. Lee ◽

Foon K. Wu-Baer ◽

Xiaohui Lin ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Essential Gene ◽

Nuclease Activity ◽

Cell Development ◽

Nuclear Body ◽

B Cell Development ◽

Immunoglobulin Gene ◽

End Resection

B cell development requires efficient proliferation and successful assembly and modifications of the immunoglobulin gene products. CtIP is an essential gene implicated in end resection and DNA repair. Here, we show that CtIP is essential for early B cell development but dispensable in naive B cells. CtIP loss is well tolerated in G1-arrested B cells and during V(D)J recombination, but in proliferating B cells, CtIP loss leads to a progressive cell death characterized by ATM hyperactivation, G2/M arrest, genomic instability, and 53BP1 nuclear body formation, indicating that the essential role of CtIP during proliferation underscores its stage-specific requirement in B cells. B cell proliferation requires phosphorylation of CtIP at T847 presumably by CDK, but not its interaction with CtBP or Rb or its nuclease activity. CtIP phosphorylation by ATM/ATR at T859 (T855 in mice) promotes end resection in G1-arrested cells but is dispensable for B cell development and class switch recombination, suggesting distinct roles for T859 and T847 phosphorylation in B cell development.

Download Full-text