Abstract

In mammals, the B-cell lineage arises from pluripotent progenitors in the bone marrow. During their development, B-cells undergo lineage specification and commitment, followed by expansion and selection. These processes are mediated by regulated changes in gene expression programmes, rearrangements of immunoglobulin (Ig) genes, and well-timed rounds of proliferation and apoptosis. Many of these processes are initiated by environmental factors including cytokines, chemokines, and cell–cell contacts. Developing B-cells process these environmental cues into stage-specific functions via signalling pathways including the PI3K, MAPK, or JAK-STAT pathway. The cytokines FLT3-Ligand and c-Kit-Ligand are important for the early expansion of the B-cell precursors at different developmental stages and conditions. Interleukin 7 is essential for commitment to the B-cell lineage and for orchestrating the Ig recombination machinery. After rearrangement of the immunoglobulin heavy chain, proliferation and apoptosis, and thus selection, are mediated by the clonal pre-B-cell receptor, and, following light chain rearrangement, by the B-cell receptor.

Introduction

B-Lymphocytes are the sole source of immunoglobulin which is indispensable for immunity. Every B-cell has a unique immunoglobulin which, when expressed on the cell surface, forms a B-cell receptor (BCR) able to specifically bind antigen and transduce signals into the cell. During development, B-cells encounter different microenvironments, which expose them to a variety of cytokines, adhesion molecules, chemokines, and self- and foreign-antigens. These are interpreted by diverse signal transduction mechanisms resulting in altered gene expression and cell biology. These signalling pathways are interconnected and regulated at many levels and represent a complex and dynamic network of activating and inhibitory signals. Understanding how extracellular signals are sensed at different developmental stages has been the focus of intensive study. Here, we highlight some of the key feedforward and feedback signalling mechanisms regulating B-cell development.

The commitment to the B-cell lineage

Haematopoietic stem cells differentiate into lineage-restricted progenitors including the common lymphoid progenitors (CLPs), the antecedents of B-lymphoid cells [1,2] (Figure1A). CLPs express the cytokine receptors CD135 (Fms-like tyrosine kinase 3 — FLT3) and CD127, the α-subunit of the interleukin 7 receptor (IL7R), which bind the FMS-like tyrosine kinase 3 ligand (FLT3L) and IL7, respectively. FLT3L is important to maintain the CLP cell stage as it mediates proliferation, attenuates B-cell development, and enables development of other lineages [3,4]. FLT3 signalling via the Ras-MAPK pathway is, however, also necessary to induce the expression of IL7R. In addition, it inhibits the expression of the suppressors of cytokine signalling 2 and 3 (SOCS-2 and -3), which block signal transduction by the IL7R-associated Janus Kinase 2 (JAK2) to STAT5 [4]. IL7 and FLT3L may act synergistically to promote proliferation and also survival at this developmental stage [5,6]. IL7 is a crucial cytokine in B-cell development and mice lacking IL7R or the signal transduction factor STAT5 have a severe impairment in B-cell development [710]. Notably, IL7 plays different roles depending on the developmental stage; it is critical in the developmental commitment to the B-cell lineage at early stages; at later stages, it controls immunoglobulin recombination orchestrating the survival and developmental progression of B-cells.

In early development, IL7 has been shown to be essential for the survival of CLPs and to contribute to their expansion in vitro and in vivo in a dose-dependent manner. At high concentrations, IL7 induces B-cell development by the induction of a B-lineage gene expression programme including the transcription factors early B-cell factor (EBF) and paired box protein 5 (PAX5) [7,1013]. A recent study suggested that IL7 promoted mainly the survival but not proliferation and to be permissive for B-lineage commitment [14]. In this study, the overexpression of FLT3L was shown to mediate the proliferation of CLPs and, surprisingly, to partially rescue B-cell development in IL7-deficient mice. This suggests a redundancy of IL7 and FLT3L to induce B-lineage commitment, at least upon overexpression. While FLT3L could possibly also activate STAT5 [15] and induce EBF expression, the molecular mechanisms remain unclear. Besides FLT3L, unknown factors provided by the bone marrow environment or thymic stromal lymphopoietin (TSLP), which shares the same receptor, could partially substitute for IL7 [16].

PAX5 is the master regulator of B-lineage commitment [17,18]. Expression of PAX5 is preceded by the expression of the transcription factor EBF [1921]. A critical amount of stable EBF expression is necessary for the induction of PAX5 and is dependent on sufficient IL7 signalling, thus setting a ligand-concentration sensitive threshold for B-cell commitment [22,23]. Forkhead box (FOXO) transcription factors are essential to sustain EBF expression, and, in turn, EBF expression sustains high levels of FOXO as a positive feedback mechanism [24]. FOXO transcription factors are inactivated by Phosphatidylinositol-3-Kinase (PI3K)-dependent phosphorylation mediated by the protein kinase B (AKT). While IL7R is considered to signal mainly via STAT5 [5,23], high levels of FLT3L can stimulate PI3K-mediated inactivation of FOXO that could attenuate developmental progression (Table 1 and Figure 1B,C). These molecular mechanisms in CLP are incompletely understood and could be explored further using novel cell culture methods of primary cells and powerful methods for single-cell analysis [12]. Once PAX5 is expressed in sufficient quantities it directs, in cooperation with EBF, the suppression of genes necessary for NK, DC, or T-lineage differentiation, and induces a B-lineage-specific transcriptional programme [2528]. FLT3, which is crucial to maintain and expand the early CLP stage, is among the genes inhibited by PAX5 [3], and thus initiates its own down-regulation in a forward inhibitory loop via IL7R-EBF-PAX5 (Figure1B).

Developmental stages and molecular regulation of B-cells in the bone marrow.

Figure 1.
Developmental stages and molecular regulation of B-cells in the bone marrow.

(A) Developmental stages of B-cells in the bone marrow. Nomenclature and surface marker expression are adapted from the Basel nomenclature referring to the expression of c-Kit, CD25, and IgM, while further markers have been added including CD19, FLT3, and IL7R. In red in italics is an alternative commonly used nomenclature indicated, which uses different surface markers to define developmental stages of B-cells (for review and comparison, see [29]). (B) Overview of active signalling pathways at the transition from CLPs to Pre-BI cells. (C) Molecular regulation circuit driving early B-lineage differentiation/commitment.

Figure 1.
Developmental stages and molecular regulation of B-cells in the bone marrow.

(A) Developmental stages of B-cells in the bone marrow. Nomenclature and surface marker expression are adapted from the Basel nomenclature referring to the expression of c-Kit, CD25, and IgM, while further markers have been added including CD19, FLT3, and IL7R. In red in italics is an alternative commonly used nomenclature indicated, which uses different surface markers to define developmental stages of B-cells (for review and comparison, see [29]). (B) Overview of active signalling pathways at the transition from CLPs to Pre-BI cells. (C) Molecular regulation circuit driving early B-lineage differentiation/commitment.

Table 1
Overview of major signalling pathways controlling early B-cell development
Receptor Main pathway CLP Pro-PreB PreBI PreBII Immature B 
IL7R STAT5 [7,51], PI3K [51,69], PLCγ [41Differentiation, Proliferation, Survival [10,13,14,23Differentiation, Proliferation, Survival [14,23,70Survival, Proliferation[49,71,72]
Inhibition of Differentiation [50
Survival [49], Proliferation [67], Inhibition of Differentiation [47,50,51Low expressed 
FLT3 MAPK [4], PI3K [39], STAT3/5 [73Proliferation, Inhibition of Differentiation [3,4,14Proliferation[4Not expressed Not expressed Not expressed 
c-Kit Ras, MAPK, PI3K [40Low expression Proliferation[35Proliferation [37Not expressed Not expressed 
PreBCR/BCR Syk, ZAP70 [66], MAPK [65], PI3K [46Not expressed Not expressed Expressed late Proliferation, Differentiation [56,68,74Proliferation, Survival, Differentiation 
BAFF-R NFKB, PI3K [75Not expressed Not expressed Not expressed Not expressed Survival, Differentiation [7577
Receptor Main pathway CLP Pro-PreB PreBI PreBII Immature B 
IL7R STAT5 [7,51], PI3K [51,69], PLCγ [41Differentiation, Proliferation, Survival [10,13,14,23Differentiation, Proliferation, Survival [14,23,70Survival, Proliferation[49,71,72]
Inhibition of Differentiation [50
Survival [49], Proliferation [67], Inhibition of Differentiation [47,50,51Low expressed 
FLT3 MAPK [4], PI3K [39], STAT3/5 [73Proliferation, Inhibition of Differentiation [3,4,14Proliferation[4Not expressed Not expressed Not expressed 
c-Kit Ras, MAPK, PI3K [40Low expression Proliferation[35Proliferation [37Not expressed Not expressed 
PreBCR/BCR Syk, ZAP70 [66], MAPK [65], PI3K [46Not expressed Not expressed Expressed late Proliferation, Differentiation [56,68,74Proliferation, Survival, Differentiation 
BAFF-R NFKB, PI3K [75Not expressed Not expressed Not expressed Not expressed Survival, Differentiation [7577

Pro-pre-B-cells comprise a small heterogeneous population developing from CLPs via intermediate stages such as the B-lymphoid progenitor [30] (Figure1A). They can be regarded as the earliest B-lineage developmental stage which gradually loses the potential to give rise to other lineages [2,3136]. They express FLT3, the receptor tyrosine phosphatase CD45R (B220), and the receptor tyrosine kinase c-Kit (CD117) which binds stem cell factor (SCF) [35,37]. While pro-pre-B-cells may require FLT3L [14], SCF and IL7 are sufficient to maintain and expand the subsequent FLT3-negative pre-BI-cell stage in vitro [38]. At this stage, IL7 availability determines a critical differentiation threshold for CLPs to gradually commit to the B-cell lineage. SCF and FLT3 appear to sustain proliferation in pro-pre-B-cells and CLPs, respectively, promoting the activation of similar signalling pathways, such as MAPK and PI3K [4,39,40] (Table 1). IL7R signals may also be transduced via the unconventional Phospholipase-Cγ-Diacylglycerol (PLCγ-DAG) pathway and subsequent mTOR activation. PLCγ1/2 double deficient mice fail to generate B-cells and are arrested at the pro-preB cell stage, due to IL7 unresponsiveness and insufficient metabolic activation [41]. However, PLCγ could also potentially be activated by the tyrosine kinases FLT3 and c-Kit [42,43] promoting mTOR-dependent metabolic activation.

In addition to inducing B-lineage commitment and proliferation, IL7 also regulates B-cell survival [9] and recombination-activating gene (RAG) expression necessary for VDJ recombination [8] for further differentiation into pre-BII cells. Pre-BII-cells are defined by the up-regulation of the α-chain of the IL2 receptor, CD25 and the presence of the VDJ rearranged Ig heavy chain [44], which pairs with the surrogate light chains (λ5 and V-preB) to form the pre-B-cell receptor (pre-BCR) [45]. At the pre-BI-cell stage, IL7R signalling inhibits RAG expression via AKT-mediated phosphorylation and inactivation of FOXO1, a transcription factor that promotes RAG gene expression [4648]. Moreover, IL7 induces expression of antiapoptotic proteins Mcl1 and Bcl2 to maintain the survival of pre-BII cells and prevent premature light chain rearrangement [49]. In contrast with its effects on CLP, IL7 attenuates development [50], promotes the survival and the orderly progression through rounds of BCR rearrangement and proliferation [51]. In turn, developing B-cells regulate their response to IL7, either by diminished expression of IL7R arising from IL7R triggered phosphorylation and inactivation of FOXO transcription factors that promote IL7R transcription, or by migrating away from the cells producing IL7 [51]. In early B-cell development, this spatial separation is believed to be essential to control differentiation. Pre-BII and immature B-cells are found to reside in an environment with little IL7, characterized by the expression of the S-type Lectin Galectin-1 [52]. This environment may favour a quiescent state permissive for VDJ recombination [53], which additionally involves post-transcriptional suppression of cell-cycle progression by RNA-binding proteins [54,55].

Pro-pre-B cells and pre-BI cells show low proliferative activity [34] undergoing one or two divisions until they mature to the subsequent stage. Expression of the pre-BCR drives proliferation [56] inducing the cells to vigorously divide 2–5 times [57]. The ability to undergo VDJ recombination is inhibited at this stage by cyclin dependent kinase 2 (CDK2) -mediated phosphorylation of RAG2 which leads to its degradation by ubiquitination [58].

Heparan sulfate [59,60] and Galectin-1 [61] were suggested as potential ligands for the pre-BCR receptor and to be involved in the positive selection of successfully rearranged heavy chains. Mice deficient for Galectin-1 have a mild impairment at the pre-BII-cell stage suggesting that the Integrin/BCR/Galectin-1-mediated B-cell interaction is largely dispensable [62]. This expansion (positive selection) is rather independent of the stromal environment [57,63]. Alternatively, clustering of pre-BCRs on the cell surface may signal in the absence of ligand and drive proliferation [64]. Pre-BCR signalling proceeds via Syk/ZAP70, MAPK, and PI3K [46,65,66] and may also lower the threshold for IL7 signalling which can contribute to cell expansion in an IL7 low environment [67]. When positively selected pre-BII cells stop proliferating, they become quiescent and rearrange their light chain genes to become BCR expressing immature B-cells [68].

The BCR signalling and selection

Once pre-BII cells have rearranged their immunoglobulin light chain genes, they express a BCR of the immunoglobulin M (IgM) class on their surface and are classified as IgM+ immature B-cells. The rearrangement of immunoglobulin genes encoding for the heavy and light chain by VDJ recombination can, as predicted by models, yield theoretically up to 1018BCR specificities [78]. The bone marrow of mice is estimated to produce 10 million B-cells per day [79]. This high production rate bares the risk that some BCRs will be reactive to self-antigen. To avoid this, highly autoreactive BCRs can promote clonal deletion by apoptosis, or a state of unresponsiveness or anergy [8083]. Approximately 60% of the newly generated immature B-cell repertoire in humans is deleted suggesting that many clones are autoreactive and that a stringent purging mechanism must be operative throughout life to avoid the generation of autoreactive B-cells [84,85].

At this stage of B-cell development, when emerging IgM+ B-cell clones are probed for auto-reactivity of their BCR, regulation of the amount of signals transduced via the BCR is crucial. The absence of a signal from the BCR leads to cell death due to the absence of survival signals. Too strong signals, however, lead to anergy (unresponsiveness) or the deletion of respective clones. Therefore, BCR signalling is mediated by a tightly balanced interplay of activating and inhibitory pathways to adjust a proper BCR signalling outcome allowing the deletion of strongly autoreactive B-cell clones, without compromising the repertoire [86,87].

The IgM C-Terminal cytoplasmic tail is short, consisting of only 25 amino acids. The BCR cytoplasmic tail associates with Igα (CD79a encoded by the mb1 gene) and Igβ (CD79b) [88,89], which are essential to promote signal transduction. Igα and Igβ contain immunoreceptor tyrosine-based activation motifs (ITAM YxxI/L) [90], a substrate for the Src family tyrosine kinases. Phosphorylation of ITAM tyrosines recruits Syk, which, in turn, becomes phosphorylated by Src tyrosine kinases. Syk is a central kinase for BCR signal transduction inducing a broad phosphorylation cascade via PLCγ and PI3K [9193]. PI3K converts phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), which allows recruitment and clustering of further signalling complexes at the plasma membrane. The PI3K pathway has emerged as one of the major pathways regulating B-cell development, survival, and function [9497]. Downstream effects regulated by active PI3K include a positive effect on survival, proliferation, growth, and metabolism in various cellular systems, in part, through its downstream target AKT [98].

Prominent inhibitory regulators comprise different classes of phosphatases reverting or preventing phosphorylation of ITAM motifs. Inhibitory receptors contain an immune receptor tyrosine-based inhibitory motif (ITIM) capable of binding the SH2 domains of tyrosine and lipid phosphatases. Examples of this class include Sialic acid-binding immunoglobulin-type lectins (SIGLEC) CD22 [99], Siglec-G [100,101]; C-type lectins like CD72 [102]; and members of the inhibitory Fc receptors [103]. Upon BCR ligation and subsequent phosphorylation, they recruit the tyrosine phosphatase SHP-1 and the SH2 domain containing inositol phosphatase (SHIP) and limit further signal transduction [104,105].

The genetic deletion of the BCR in mature B-cells leads to cell death [106], indicating continual signalling by the BCR in the absence of antigen binding, is necessary for B-cells to survive. BCR deletion can be rescued by activation of the PI3K pathway, highlighting its function in promoting survival of B-cells after so-called ‘tonic BCR stimulation’ [107].

Strong signalling via PI3K leads, at the immature B-cell stage, to down-regulation of the RAG genes via inhibition of FOXO transcription factors. This stops further gene rearrangements in developing immature B-cells which exit the bone marrow after selection [47,106108]. One possible mechanism of negative selection of autoreactive B-cells could be that strong auto-reactivity leads to BCR internalization and thus absence of PI3K pro-survival signalling [109112]. The absence of PI3K leads to higher activity of FOXO, which, in turn, activates the proapoptotic Bcl-2-like protein 11 (BIM), resulting in apoptosis in developing immature B-cells [113,114]. B-cells can rescue themselves from cell death by the re-induction of RAG genes, in fact via the same transcription factor FOXO that induces apoptosis. This results in another attempt of light chain rearrangement to express a non-autoreactive BCR (a process called receptor editing [81]). Thus the pro-apoptotic activities of FOXO have to be counteracted to prolong the survival of these cells to allow editing. Potential microenvironments for B-cells undergoing selection within the bone marrow have been suspected to exist [115] and to provide pro-survival factors like the B-cell activating factor (BAFF) [76] or IL4 [116] to developing immature B-cells. Since immature B-cells are only minimally responsive to IL7 [117], BAFF, B-cell stimulating a ligand of the tumour necrosis factor family [118,119], has been suggested to promote the survival of immature B-cells [76,77]. Moreover, it has been shown to be important for the selection and maturation to mature/transitional B-cells [7577,120]. However, such a specific niche providing BAFF or other survival factors has yet to be identified, although the myeloid lineage, NK-cells, and Basophils have been suggested to play a role in forming such a niche [119,121,122].

Closing remarks

We have discussed, in brief, the surface receptors and pathways that act during B-cell ontogeny due to developmental stage-specific expression. C-Kit is expressed upon commitment to the B-cell lineage, while FLT3 is down-regulated (Table 1). Both receptors signal via the Ras-MAPK pathway [4,40] and seem to have overlapping functions to stimulate proliferation at different stages of B-cell development, independently of the transcriptional programme of the cells. IL7 is the major cytokine driving the differentiation of the B-lymphoid lineage by regulating its early gene expression programme, providing survival cues and orchestrating VDJ recombination. Once the pre-BCR and later BCR is expressed, proliferation and survival and therefore selection are governed by the signalling quality of these receptors [46,65]. Thus, the differentiation programme of B-cells is punctuated by waves of proliferation directed by environmental signals and by the Immunoglobulin genes. Interestingly, the dependence of B-cell development on IL7 is observed only in mice, in humans IL7 is dispensable for B-cell development [123125]. It is possible that other factors (like higher expression of FLT3L) promote B-cell development and target the same signal transduction pathways in humans and remain to be characterized. Failed developmental regulation and quality control of the generated repertoire, induced by spontaneous mutations during development or inherited genetic defects, can lead to a variety of immunodeficiency, autoimmune, and tumorous diseases (reviewed elsewhere [126129]). Therefore, understanding the basic regulatory mechanisms of B-cell development is essential for future therapeutic designs.

Abbreviations

     
  • BAFF

    B-cell activating factor

  •  
  • CLPs

    common lymphoid progenitors

  •  
  • EBF

    early B-cell factor

  •  
  • FLT3

    Fms-like tyrosine kinase 3

  •  
  • FLT3L

    FMS-like tyrosine kinase 3 ligand

  •  
  • FOXO

    Forkhead box

  •  
  • IgM

    immunoglobulin M

  •  
  • IL7R

    interleukin 7 receptor

  •  
  • PAX5

    paired box protein 5

  •  
  • PI3K

    phosphatidylinositol-3-kinase

  •  
  • pre-BCR

    pre-B-cell receptor

  •  
  • RAG

    recombination-activating gene

  •  
  • SCF

    stem cell factor

  •  
  • TSLP

    thymic stromal lymphopoietin

Funding

Work in the author's laboratory is supported by the Biotechnology and Biological Sciences Research Council.

Acknowledgements

We thank Alexander Saveliev, Fiamma Salerno, Elisa Monzon-Casanova, and Lena Lampe for their discussion.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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