ReviewThe many roles of IL-7 in B cell development; Mediator of survival, proliferation and differentiation
Highlights
► IL-7R signaling in B cells. ► The role of IL-7 during early B cell development. ► IL-7 regulation of B cell survival, proliferation and maturation. ► IL-7 regulation of V(D)J recombination. ► Regulation, modification and termination of IL-7R signaling.
Introduction
B cells are derived from hematopoietic stem cells (HSCs) in a process by which cells progressively develop B cell traits while repressing traits of other lineages. During development, progenitor B cells undergo rearrangement of their immunoglobulin (Ig) loci in a stepwise and reproducible fashion, whereby recombination of the heavy chain (HC) genes occurs in pro-B cells followed by recombination of the light chain (LC) genes in pre-B cells. Binding of μHC proteins with surrogate LC proteins λ5 and VpreB leads to surface expression of the pre-B cell receptor (pre-BCR) on large pre-B cells, which initiates survival, proliferation and maturation signals via Igα and Igβ signaling subunits. Small resting pre-B cells exit the cell cycle and once again begin the recombination process, leading to rearrangement of the LC proteins. LC proteins associate with μHC proteins to form the B cell receptor (BCR), which is first expressed on immature B cells. Immature B cells undergo positive and negative selection in the bone marrow (BM) and subsequently exit into the periphery where they undergo additional selection prior to becoming functional mature B cells capable of responding to antigen.
B lymphopoiesis takes place in niches within the fetal liver (FL) or BM, which provide the structure for development to proceed, as well as the necessary chemokines and cytokines that regulate signal transduction pathways in receptive cells. Initiation of signaling pathways in turn activate transcription factors (TFs) that function to induce or repress the expression of various target genes that modulate B cell survival, proliferation and differentiation. Interleukin-7 (IL-7) is a key cytokine during B cell development and is produced by stromal cells in the FL, BM, spleen and thymus. IL-7 receptor (IL-7R) signaling leads to the proliferation and survival of B cell progenitors as well as aids in the commitment of cells to the B lineage. Mice with targeted deletions of IL-7 or the IL-7R display a severe block at the early pro-B cell stage of development [1], [2]. The peripheral B cells that exist in these mice appear to have originated during fetal development, a time during which B lymphopoiesis is not absolutely dependent on IL-7. Thymic stromal lymphopoietin (TSLP) is a cytokine that possesses a number of characteristics in common with IL-7 and its receptor is composed of the IL-7Rα chain and TSLPR chain. Fetal derived pro-B and pre-B cells respond to TSLP, while in adult BM, only pre-B cells are TSLP-responsive [3], [4]. TSLP was thought to substitute for IL-7 during fetal development, because transgenic expression of TSLP in IL-7−/− mice restored B cell development during fetal and adult life [5]. However, IL-7−/−/TSLP−/− mice did not show enhanced defects during fetal B cell development and, instead, it was the absence of IL-7 and fms-related tyrosine kinase-3 ligand (Flt-3L) that completely abolished both fetal and adult development of B cells [6], [7]. Flt-3L was also able to recover the development of residual B cells present in IL-7Rα deficient mice [3]. IL-7 transgenic mice displayed increased numbers of immature and mature B cells in the BM, as well as extramedullary B lymphopoiesis whereby pro-B and pre-B cells were observed in the spleen, blood, and lymph nodes, and ultimately lead to lymphoproliferative disorders [8].
IL-7 is absolutely essential for murine B cell development, however, in humans it was thought that this was not the case. Genetic mutations in humans that disrupted the IL-7R led to X-linked severe combined immunodeficiency disease (X-SCID), which is characterised by the absence of T cells and natural killer (NK) cells but normal B cell numbers [9]. However, similar to mice, these B cells appear to be the result of fetal or neonatal development. In vitro, human B cells can be generated from fetal BM as well as cord blood (CB) in the absence of IL-7 [10], [11]. However, human B cell precursors express the IL-7R and displayed increased proliferation and survival in response to IL-7 that was mediated by Signal Transducer and Activator of Transcription-5 (STAT5) [12]. IL-7 also greatly increased the production of B cells in co-cultures containing human BM stroma and either CB or adult BM HSCs, while only neonatal CB was able to give rise to B cell progenitors independent of IL-7 [11]. In humans, TSLP cannot substitute for IL-7, while Flt-3L is able to support IL-7-independent B lymphopoiesis from neonatal CB [11], [13].
As important as the signaling pathways initiated by IL-7 and other cytokines, are the mechanisms that exist to regulate and terminate these signals. The suppressor of cytokine signaling (SOCS) family of proteins are key regulators of cytokine signals and are essential for the development and function of a variety of hematopoietic lineages (reviewed in [14]). SOCS proteins contain three functional domains: a central SH2 domain that is necessary for binding to phosphotyrosine residues on target proteins; a C-terminal domain, termed the SOCS box, which is involved in ubiquitin-mediated proteasomal degradation via elongins B and C; and an N-terminal domain whose function remains largely undefined. SOCS proteins bind directly to Janus Associated Kinase (JAK) and STAT proteins, as well as cytokine receptor chains, and prevent their interaction as well as target them for destruction. SOCS proteins are often induced by the same signaling pathway that they inhibit, providing a negative feedback loop that functions to limit receptor activation.
This review will focus on the signal transduction pathways activated downstream of the IL-7R, as well as how IL-7R signals are translated into the observed physiological outcomes of survival, proliferation and differentiation. We will also discuss the other surface proteins, signaling molecules and TFs that assist in mediating the effects of IL-7 in developing B cells. Finally, we will describe the mechanisms that exist both extrinsically and intrinsically to modulate and terminate IL-7R signals, ensuring that B cell development proceeds efficiently.
Section snippets
JAK/STAT and Src activation
The IL-7R is a heterodimer composed of the IL-7Rα chain and the common γ (γc) chain. The γc chain is a shared component of the receptors for IL-2, IL-4, IL-9, IL-15 and IL-21, while the IL-7Rα chain can also dimerize with the TSLPR chain to form the receptor for TSLP. The γc chain is expressed by a variety of hematopoietic cells and is essential for initiating signals downstream of the IL-7R; however, it is the α chain, which is predominantly expressed by lymphoid cells, that confers receptor
IL-7 synergy with other early co-factors
Developing B cells rely on a variety of factors that provide signals independently or in conjunction with those from the IL-7R. Stem cell factor (SCF, c-Kit-Ligand) binds c-Kit and is required during the earliest stages of hematopoietic development. SCF acts directly on developing B cells and, in vitro, worked synergistically with IL-7 to increase the numbers of pro-B cells in culture [44]. Flt-3L, and its receptor Flt-3, also play important roles in enhancing the survival and proliferation of
Cell survival
One of the main functions of IL-7R signaling during B cell development is to promote cell survival by regulating the localization and interaction of anti-apoptotic (Bcl-2, Bcl-xL and Mcl-1) and pro-apoptotic (Bax, Bad and Bim) factors. Both the JAK/STAT and PI3K/Akt pathways play key roles in mediating survival responses. IL-7R signaling enhances pro-B cell survival by increasing the ratio of Bcl-2 to Bax and, correspondingly, mice deficient for the IL-7R or JAK3 displayed increased levels of
IL-7 regulation of heavy chain recombination
Additional roles for IL-7 in promoting B cell development have been proposed based on studies demonstrating that IL-7R signaling can affect both HC and LC recombination. Several reports have noted that IL-7R activation of STAT5 promoted chromatin accessibility through histone acetylation of the distal VH genes in pro-B cells [88], [89]. In small pre-B cells, which are non-responsive to IL-7, distal VH sites were hypoacetylated and thus non-accessible, providing a possible IL-7-mediated
Modulation of IL-7R signaling by CD45 and the pre-BCR
A variety of signaling pathways are initiated in developing B cells. The factors activated by these pathways can interact with signaling molecules downstream of the IL-7R, modifying the magnitude, duration or quality of the response. B220 is the 220-kDa isoform of the surface membrane phosphatase CD45. CD45 is present on all mouse B cells, except terminally differentiated plasma blasts, as well as in varying isoforms on dendritic cells, T cells, macrophages and NK cells. CD45 dephosphorylates
Conclusion
IL-7 is a key factor that regulates B lymphopoiesis and plays multiple roles in the commitment, survival, proliferation and differentiation of B cell progenitors. During development, B cells receive both activation and inhibition signals from IL-7, which are modified by the amount of IL-7 present and the activation of other signaling pathways (Fig. 1). Certain aspects of the IL-7R signaling pathway have been well characterized, however, others have yet to be fully elucidated, including; the
Acknowledgements
This work was supported by the Canadian Institutes for Health Research. We would like to thank members of the Paige laboratory for helpful discussions and critical reading of this manuscript.
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