Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling

Key Points

  • The hallmark of B lymphopoiesis is the sequential productive genomic rearrangement of the immunoglobulin heavy chain locus (Igμ) and then the two immunoglobulin light chain loci (Igκ followed by Igλ). Before recombination of the immunoglobulin light chain loci, the expressed Igμ chain forms the pre-B cell receptor (pre-BCR), which along with the interleukin-7 receptor (IL-7R) promotes clonal expansion. However, pre-B cells must exit the cell cycle before initiating Igκ recombination. Failure to do so risks genomic instability and leukaemic transformation. Recent findings have shed light on the regulatory networks that direct proliferation and Igκ gene recombination, and ensure that they are separated during B lymphopoiesis.

  • In mice, development of B cells in the bone marrow is dependent on IL-7R signalling. IL-7R signalling activates signal transducer and activator of transcription 5 (STAT5), and this seems to promote the expression of the transcription factor early B cell factor 1 (EBF1) and cyclin D3, which are required for the specification and proliferation, respectively, of B cell lineage progenitors. The IL-7R also activates phosphoinositide 3-kinase (PI3K), which ensures cell survival.

  • IL-7R signalling represses Igκ locus recombination. Activation of PI3K promotes degradation of forkhead box protein O (FOXO) transcription factors, which are necessary for inducing the recombination-activating genes (RAGs). Concomitantly, IL-7-activated STAT5 binds to the Igκ intronic enhancer, where it recruits histone methyltransferases that alter chromatin structure and block accessibility of the Igκ locus to the recombination machinery.

  • In contrast to the IL-7R, the pre-BCR promotes Igκ gene recombination. Induction of the transcription factors E2A, interferon-regulatory factor 4 (IRF4) and IRF8 open the Igκ locus to recombination, whereas activation of p38 kinase enhances RAG expression via FOXO factors. Because STAT5 represses the Igκ locus, and PI3K prevents RAG induction, Igκ gene recombination requires both the attenuation of IL-7R signalling and productive signalling through the pre-BCR.

  • In pre-B cells, signalling by both the IL-7R and pre-BCR could risk genomic instability. However, there are a series of feedforward and feedback loops between these two signalling systems that ensure that only one receptor predominantly directs key cellular dynamics at any one time.

Abstract

The development of B cells is dependent on the sequential DNA rearrangement of immunoglobulin loci that encode subunits of the B cell receptor. The pathway navigates a crucial checkpoint that ensures expression of a signalling-competent immunoglobulin heavy chain before commitment to rearrangement and expression of an immunoglobulin light chain. The checkpoint segregates proliferation of pre-B cells from immunoglobulin light chain recombination and their differentiation into B cells. Recent advances have revealed the molecular circuitry that controls two rival signalling systems, namely the interleukin-7 (IL-7) receptor and the pre-B cell receptor, to ensure that proliferation and immunoglobulin recombination are mutually exclusive, thereby maintaining genomic integrity during B cell development.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: B lymphopoiesis.
Figure 2: The IL-7R and pre-BCR coordinate proliferation with Igκ gene recombination in B lineage cells.
Figure 3: Self-reinforcing network regulating pro-B cell survival.
Figure 4: Regulation of Igκ locus accessibility.
Figure 5: Regulatory network orchestrating the pre-B cell developmental checkpoint.
Figure 6: Movement of B cell progenitors through successive bone marrow niches.

Similar content being viewed by others

References

  1. Schlissel, M. S. Regulating antigen-receptor gene assembly. Nature Rev. Immunol. 3, 890–899 (2003).

    Article  CAS  Google Scholar 

  2. Clark, M. R., Cooper, A. B., Wang, L. & Aifantis, I. The pre-B cell receptor in B cell development: recent advances, persistent questions and conserved mechanisms. Curr. Top. Microbiol. Immunol. 290, 87–104 (2005).

    CAS  PubMed  Google Scholar 

  3. Herzog, S., Reth, M. & Jumaa, H. Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signaling. Nature Rev. Immunol. 9, 195–205 (2009).

    Article  CAS  Google Scholar 

  4. Zhang, L., Reynolds, T. L., Shan, S. & Desiderio, S. Coupling of V(D)J recombination to cell cycle suppresses genomic instability and lymphoid tumorigenesis. Immunity 34, 163–174 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Corfe, S. A. & Paige, C. J. The many roles of IL-7 in B cell development; Mediator of survival, proliferation and differentiation. Semin. Immunol. 24, 198–208 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Peschon, J. J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994). This study demonstrates the importance of IL-7 signalling in murine B lymphopoiesis.

    Article  CAS  PubMed  Google Scholar 

  7. Jensen, C. T. et al. FLT3 ligand and not TSLP is the key regulator of IL-7-independent B-1 and B-2 B lymphopoiesis. Blood 112, 2297–2304 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Clark, M. R. Flippin' lipids. Nature Immunol. 12, 373–375 (2011).

    Article  CAS  Google Scholar 

  9. Siggs, O. M. et al. The P4 ATPase ATP11c is essential for B lymphopoiesis in adult bone marrow. Nature Immunol. 12, 434–440 (2011).

    Article  CAS  Google Scholar 

  10. Yabas, M. et al. ATP11c is critical for phosphatidylserine internalization and B lymphocyte differentiation. Nature Immunol. 12, 441–449 (2011).

    Article  CAS  Google Scholar 

  11. Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T B+ NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Giliani, S. et al. Interleukin-7 receptor α (IL-7Rα) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients. Immunol. Rev. 203, 110–126 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. O'Shea, J. J. & Plenge, R. M. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36, 542–550 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chou, W. C., Levy, D. E. & Lee, C. K. STAT3 positively regulates an early step in B-cell development. Blood 108, 3005–3011 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yao, Z. et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Natl Acad. Sci. USA 103, 1000–1005 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goetz, C. A., Harmon, I. R., O'Neil, J. J., Burchill, M. A. & Farrar, M. A. STAT5 activation underlies IL7 receptor-dependent B cell development. J. Immunol. 172, 4770–4778 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Mandal, M. et al. Ras orchestrates cell cycle exit and light chain recombination during early B cell development. Nature Immunol. 10, 1110–1117 (2009).

    Article  CAS  Google Scholar 

  18. Johnson, S. E., Shah, N., Panoskaltsis-Mortari, A. & LeBien, T. W. Murine and human IL-7 activate STAT5 and induce proliferation of normal human pro-B cells. J. Immunol. 175, 7325–7331 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Cooper, A. B. et al. A unique function for cyclin D3 in early B cell development. Nature Immunol. 7, 489–497 (2006).

    Article  CAS  Google Scholar 

  20. Sherr, C. J. & Roberts, J. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Ciemerych, M. A. & Sicinski, P. Cell cycle in mouse development. Oncogene 24, 2877–2898 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004). This study shows that the cyclin D proteins are primarily needed for haematopoiesis and are dispensable for the proliferation of most other non-haematopoietic cell lineages.

    Article  CAS  PubMed  Google Scholar 

  23. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Powers, S. E. et al. Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression. J. Exp. Med. 209, 2199–2213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sicinska, E. et al. Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 4, 451–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Peled, J. U. et al. Requirement for cyclin D3 in germinal center formation and function. Cell Res. 20, 631–646 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Lam, E. W. et al. Cyclin D3 compensates for loss of cyclin D2 in mouse B-lymphocytes activated via the antigen receptor and CD40. J. Biol. Chem. 275, 3479–3484 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Solvason, N. et al. Cyclin D2 is essential for BCR-mediated proliferation and CD5 B cell development. Int. Immunol. 12, 631–638 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Johnson, K. et al. Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity 28, 335–345 (2008). This paper elaborates a molecular framework for coupling the attenuation of IL-7 signalling with the expression of IRF4 in promoting pre-B cell differentiation.

    Article  CAS  PubMed  Google Scholar 

  30. Ma, S. et al. Ikaros and Aiolos inhibit pre-B cell proliferation by directly suppressing c-Myc expression. Mol. Cell. Biol. 30, 4149–4158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakayama, K. et al. Mice lacking p27kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia and pituitary tumors. Cell 85, 707–720 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Malin, S. et al. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nature Immunol. 11, 171–179 (2010).

    Article  CAS  Google Scholar 

  33. Jiang, Q. et al. Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members. Mol. Cell. Biol. 24, 6501–6513 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bednarski, J. J. et al. RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation. J. Exp. Med. 209, 11–17 (2011).

    Article  PubMed  CAS  Google Scholar 

  35. Milne, C. D. & Paige, C. J. IL-7: a key regulator of B lymphopoiesis. Semin. Immunol. 18, 20–30 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Ochiai, K. et al. A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation. Nature Immunol. 13, 300–307 (2012). This study describes the assembly of a gene regulatory network that orchestrates the pre-B cell developmental checkpoint.

    Article  CAS  Google Scholar 

  37. Corcoran, A. E. et al. The interleukin-7 receptor α chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. EMBO J. 15, 1924–1932 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ramadani, F. et al. The PI3K isoforms p110α and p110δ are essential for pre-B cell receptor signaling and B cell development. Sci. Signal. 3, ra60 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Fruman, D. A. et al. Impaired B cell development and proliferation in absence of phosphoinositide 3- kinase p85α. Science 283, 393–397 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Suzuki, H. et al. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase. Science. 283, 390–392 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Clayton, E. et al. A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation. J. Exp. Med. 196, 753–763 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jou, S.-T. et al. Essential, nonredundant role of the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22, 8580–8591 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031–1034 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Huntington, N. D. et al. Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim sustains B lymphopoiesis in the absence of IL-7. Int. Immunol. 21, 715–725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kruse, E. A. et al. MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation. J. Immunol. 183, 261–269 (2009).

    Article  PubMed  Google Scholar 

  46. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell 116, 205–219 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Essafi, A. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317–2329 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Castellano, E. & Downward, J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2, 261–274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Medina, K. L. et al. Assembling a gene regulatory network for specification of the B cell fate. Dev. Cell 7, 607–617 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Pongubala, J. M. et al. Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5. Nature Immunol. 9, 203–215 (2008).

    Article  CAS  Google Scholar 

  52. Singh, H., Medina, K. L. & Pongubala, M. R. Contigent gene regulatory networks and B cell fate specification. Proc. Natl Acad. Sci. USA 102, 4949–4953 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nutt, S. L. & Kee, B. L. The transcriptional regulation of B cell lineage commitment. Immunity 26, 715–725 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Gyory, I. et al. Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells. Genes Dev. 26, 668–682 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Dengler, H. S. et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nature Immunol. 12, 1388–1398 (2008).

    Article  CAS  Google Scholar 

  56. Fahlman, C., Blomhoff, H. K., Veiby, O. P., McNiece, I. K. & Jacobsen, S. E. Stem cell factor and interleukin-7 synergize to enhance early myelopoiesis in vitro. Blood 84, 1450–1456 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Fahl, S. P., Crittenden, R. B., Allman, D. & Bender, T. P. c-Myb is required for pro-B cell differentiation. J. Immunol. 183, 5582–5592 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Kosan, C. et al. Transcription factor miz-1 is required to regulate interleukin-7 receptor signaling at early commitment stages of B cell differentiation. Immunity 33, 917–928 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Hardin, J. D. et al. Bone marrow B lymphocyte development in c-abl-deficient mice. Cell. Immunol. 165, 44–54 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Schwartzberg, P. L. et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 65, 1165–1175 (1991).

    Article  CAS  PubMed  Google Scholar 

  61. Tybulewicz, V. L., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-Abl proto-oncogene. Cell 65, 1153–1164 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Brightbill, H. & Schlissel, M. S. The effects of c-Abl mutation on developing B cell differentiation and survival. Int. Immunol. 21, 575–585 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lam, Q. L. et al. Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice. Int. Immunol. 19, 267–276 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Gu, J. J., Zhang, N., He, Y. W., Koleske, A. J. & Pendergast, A. M. Defective T cell development and function in the absence of Abelson kinases. J. Immunol. 179, 7334–7344 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Zipfel, P. A. et al. The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19. J. Immunol. 165, 6872–6881 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Roose, J. P. et al. T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression. PLoS Biol. 1, E53 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Kharbanda, S. et al. Activation of the c-Abl tyrosine kinase in the stress response to DMA-damaging agents. Nature 376, 785–788 (2002).

    Article  Google Scholar 

  68. Kondo, M., Akashi, K., Domen, J., Sugamura, K. & Weissman, I. L. Bcl-2 rescues T lymphopoiesis, but not B or NK cell development, in common γ chain-deficient mice. Immunity 7, 155–162 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Roessler, S. et al. Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Mol. Cell. Biol. 27, 579–594 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Dias, S., Mansson, R., Gurbuxani, S., Sigvardsson, M. & Kee, B. L. E2A proteins promote development of lymphoid-primed multipotent progenitors. Immunity 29, 217–227 (2005).

    Article  CAS  Google Scholar 

  71. Kikuchi, K., Lai, A. Y., Hsu, C. L. & Kondo, M. IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF. J. Exp. Med. 201, 1197–1203 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Rothenberg, E. V., Moore, J. E. & Yui, M. A. Launching the T-cell-lineage developmental programme. Nature Rev. Immunol. 8, 9–21 (2008).

    Article  CAS  Google Scholar 

  73. Herzog, S. et al. SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway. Nature Immunol. 9, 623–631 (2008).

    Article  CAS  Google Scholar 

  74. Amin, R. H. & Schlissel, M. S. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nature Immunol. 9, 613–622 (2008). References 73 and 74 demonstrate the role of PI3K and the FOXO transcription factors in regulating Rag gene expression during B lymphopoiesis.

    Article  CAS  Google Scholar 

  75. Lee, J. & Desiderio, S. Cyclin A/CDK2 regulates V(D)J recombination by coordinating RAG-2 accumulation and DNA repair. Immunity 11, 771–781 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Li, Z., Dordai, D. I., Lee, J. & Desiderio, S. A conserved degradation signal regulates RAG-2 accumulation during cell division and links V(D)J recombination to the cell cycle. Immunity 5, 575–589 (1996).

    Article  PubMed  Google Scholar 

  77. Jiang, H. et al. Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle. Mol. Cell 18, 699–709 (2005). This study demonstrates that the mechanisms that regulate cell cycle progression also regulate the stability of Rag2.

    Article  CAS  PubMed  Google Scholar 

  78. Johnson, K. et al. IL-7 functionally segregates the pro-B cell stage by regulating transcription of recombination mediators across cell cycle. J. Immunol. 188, 6084–6092 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Reynaud, D. et al. Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nature Immunol. 9, 927–936 (2008).

    Article  CAS  Google Scholar 

  80. Alkhatib, A. et al. FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination. J. Exp. Med. 209, 395–406 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bertolino, E. et al. Regulation of interleukin 7-dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5. Nature Immunol. 6, 836–843 (2005).

    Article  CAS  Google Scholar 

  82. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. A. B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423–426 (1991). This paper demonstrates the importance of the pre-BCR in B lymphopoiesis.

    Article  CAS  PubMed  Google Scholar 

  83. Shimizu, T., Mundt, C., Licence, S., Melchers, F. & Martensson, I. VpreB1/VpreB2/λ5 triple-deficient mice show impaired B cell development but functional allelic exclusion of the IgH locus. J. Immunol. 168, 6286–6293 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Pelanda, R., Braun, U., Hobeika, E., Nussenzweig, M. C. & Reth, M. B cell progenitors are arrested in maturation but have intact V(D)J recombination in the absence of Ig-α and Ig-β. J. Immunol. 169, 865–872 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Gong, S. & Nussenzweig, M. C. Regulation of an early developmental checkpoint in the B cell pathway by Ig-β. Science 272, 411–414 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Meixlsperger, S. et al. Conventional light chains inhibit the autonomous signaling capacity of the B cell receptor. Immunity 26, 323–333 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Ohnishi, K. & Melchers, F. The nonimmunoglobulin portion of λ5 mediates cell-auttonomous pre-B cell receptor signaling. Nature Immunol. 4, 849–856 (2003).

    Article  CAS  Google Scholar 

  88. Bankovich, A. J. et al. Structural insight into pre-B cell receptor function. Science 316, 291–294 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Vettermann, C. et al. A unique role for the lambda5 non-immunoglobulin tail in early B lymphocyte development. J. Immunol. 181, 3232–3242 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Kohler, F. et al. Autoreactive B cell receptors mimic autonomous pre-B cell receptor signaling and induce proliferation of early B cells. Immunity 29, 912–921 (2008).

    Article  PubMed  CAS  Google Scholar 

  91. Bradl, H., Wittmann, J., Milius, D., Vettermann, C. & Jack, H. M. Interaction of murine precursor B cell receptor with stroma cells is controlled by the unique tail of lambda 5 and stroma cell-associated heparan sulfate. J. Immunol. 171, 2338–2348 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Gauthier, L., Rossi, B., Roux, F., Termine, E. & Schiff, C. Galectin-1 is a stromal cell ligand of the pre-B cell receptor (BCR) implicated in synapse formation between pre-B and stromal cells and in pre-BCR triggering. Proc. Natl Acad. Sci. USA 99, 13014–13019 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Espeli, M., Mancini, S. J. C., Breton, C., Poirier, F. & Schiff, C. Impaired B-cell development at the pre-BII-cell stage in galectin-1-deficient mice due to inefficient pre-BII/stromal cell interactions. Blood 113, 5878–5886 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Mourcin, F. et al. Galectin-1-expressing stromal cells constitute a specific niche for pre-BII cell development in mouse bone marrow. Blood 117, 6552–6561 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Keenan, R. A. et al. Censoring of autoreactive B cell development by the pre-B cell receptor. Science 321, 696–699 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Eschbach, C. et al. Efficient generation of B lymphocytes by recognition of self-antigens. Eur. J. Immunol. 41, 2397–2403 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Doughty, C. A. et al. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107, 4458–4465 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ward, P. S. & Thompson, C. B. Signaling in control of cell growth and metabolism. Cold Spring Harb. Perspect. Biol. 4, a006783 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Lazorchak, A. S. et al. Sin1-mTORC2 suppresses rag and Il7r gene expression through Akt2 in B cells. Mol. Cell 39, 433–443 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rathmell, J. C. et al. Akt-directed glucose matabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol. Cell. Biol. 23, 7315–7328 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gottlob, K. et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. DeBerardinis, R. J. & Thompson, C. B. Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148, 1132–1144 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Powell, D. J. & Delgoffe, G. M. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33, 301–311 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Iritani, B. M. & Eisenman, R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl Acad. Sci, USA 1999, 13180–13185 (1999).

    Article  Google Scholar 

  105. Grumont, R. J., Strasser, A. & Gerondakis, S. B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-κB regulated c-myc transcription. Mol. Cell 10, 1283–1294 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Dang, C. V. MYC on the path to cancer. Cell 149, 22–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nature Immunol. 9, 405–414 (2008).

    Article  CAS  Google Scholar 

  108. Sandoval, G. J. et al. Cutting edge: cell-autonomous control of IL-7 response revealed in a novel stage of precursor B cells. J. Immunol. 190, 2485–2489 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Yasuda, T. et al. Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity 28, 499–508 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Rolink, A., Winkler, T., Melchers, F. & Andersson, J. Precursor B cell receptor-dependent B cell proliferation and differentiation does not require the bone marrow or fetal liver environment. J. Exp. Med. 191, 23–31 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Parker, M. J. et al. The pre-B-cell receptor induces silencing of VpreB and λ5 transcription. EMBO J. 24, 3895–3905 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Melchers, F. The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoire. Nature Rev. Immunol. 5, 578–584 (2005).

    Article  CAS  Google Scholar 

  113. Melchers, F. et al. Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells. Immunol. Rev. 175, 33–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. van Loo, P. F., Dingjan, G. M., Maas, A. & Hendriks, R. W. Surrogate-light-chain silencing is not critical for the limitation of pre-B cell expansion but is for the termination of constitutive signaling. Immunity 27, 1–13 (2007). This study demonstrates that downregulation of pre-BCR expression is not necessary for pre-B cell cycle exit or pre-B cell development.

    Article  CAS  Google Scholar 

  115. Jumaa, H. et al. Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 11, 547–554 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Xu, S., Lee, K. G., Huo, J., Kurosaki, T. & Lam, K. P. Combined deficiencies in Bruton tyrosine kinase and phospholipase Cγ2 arrest B-cell development at a pre-BCR+ stage. Blood 109, 3377–3384 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Bai, L. et al. Phospholipase Cγ2 contributes to light-chain gene activation and receptor editing. Mol. Cell. Biol. 27, 5957–5967 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Thompson, E. C. et al. Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits. Immunity 26, 335–344 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Heng, T. S., Painter, M. W. & Consortium, I. G. P. The Immunological Genome Project: networks of gene expression in immune cells. Nature Immunol. 9, 1091–1094 (2008).

    Article  CAS  Google Scholar 

  120. Iritani, B. M., Forbush, K. A., Farrar, M. A. & Perlmutter, R. M. Control of B cell development by Ras-mediated activation of Raf. EMBO J. 16, 7019–7031 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mandal, M. et al. Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid. Proc. Natl Acad. Sci. USA 105, 20840–20845 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ley, R., Balmanno, K., Hadfield, K., Weston, C. & Cook, S. J. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J. Biol. Chem. 278, 18811–18816 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Um, J. H. et al. Metabolic sensor AMPK directly phosphorylates RAG1 protein and regulates V(D)J recombination. Proc. Natl Acad. Sci. USA 110, 9873–9878 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Park, H. et al. Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity 36, 1–13 (2012).

    Article  CAS  Google Scholar 

  125. Stanhope-Baker, P., Hudson, K., Shaffer, A. L., Constantinescu, A. & Schlissel, M. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. Cell 85, 887–897 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Young, F. et al. Influnence of immunoglobulin heavy- and light-chain expression on B-cell differentation. Genes Dev. 8, 1043–1057 (1994).

    Article  CAS  PubMed  Google Scholar 

  127. Flemming, A., Brummer, T., Reth, M. & Jumaa, H. The adaptor protein SLP-65 acts as a tumor suppressor that limits pre-B cell expansion. Nature Immunol. 4, 38–43 (2003).

    Article  CAS  Google Scholar 

  128. Shaw, A. C., Swat, W., Ferrini, R., Davidson, L. & Alt, F. W. Activated Ras signals developmental progression of recombinase-activating gene (RAG)-deficient pro-B lymphocytes. J. Exp. Med. 189, 123–129 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Shaw, A. C., Swat, W., Davidson, L. & Alt, F. W. Induction of Ig light chain gene rearrangement in heavy chain-deficient B cells by activated Ras. Proc. Natl Acad. Sci. USA 96, 2239–2243 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kee, B. L., Quong, M. W. & Murre, C. E2A proteins: essential regulators at multiple stages of B-cell development. Immunol. Rev. 175, 138–149 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Inlay, M. A., Tian, H., Lin, T. & Xu, Y. Important roles for E protein binding sites within the immunoglobulin k chain intronic enhance in avtivating V-κJ-κ rearrangement. J. Exp. Med. 200, 1205–1211 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ronanow, W. J. et al. E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. Mol. Cell 5, 215–223 (2000).

    Google Scholar 

  133. Lazorchak, A., Jones, M. E. & Zhuang, Y. New insights into E-protein function in lymphocyte development. Trends Immunol. 26, 334–338 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Lazorchak, A. S., Schlissel, M. S. & Zhuang, Y. E2A and IRF-4/Pip promote chromatin modification and transcription of the immunoglobulin κ locus in pre-B cells. Mol. Cell. Biol. 26, 810–821 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Schlissel, M. S. Regulation of activation and recombination of the murine Igκ locus. Immunol. Rev. 200, 215–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Beck, K., Peak, M. M., Ota, T., Nemazee, D. & Murre, C. Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J. Exp. Med. 206, 2271–2284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sakamoto, S. et al. E2A and CBP/p300 act in synergy to promote chromatin accessibility of the immunoglobulin κ locus. J. Immunol. 188, 5547–5560 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Lu, R., Kay, L., Lancki, D. W. & Singh, H. IRF-4,8 orchestrate the pre-B to B transition in lymphocyte development. Genes Dev. 17, 1703–1708 (2003). This study establishes the requirement of the transcription factors IRF4 and IRF8 at the pre-B cell stage. It describes an in vitro culture system that facilitates the molecular analysis of pre-B cell differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ma, S., Pathak, S., Trinh, L. & Lu, R. Interferon regulatory factors 7 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B cell receptor and promote cell-cycle withdrawal in pre-B cell development. Blood 111, 1396–1403 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mandal, M. et al. Epigenetic repression of the Ig-κ locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nature Immunol. 12, 1212–1220 (2011). These authors demonstrate that STAT5 can function as an important transcriptional repressor in B lymphophoiesis.

    Article  CAS  Google Scholar 

  141. Xu, C.-R. & Feeney, A. J. The epigenetic profile of Ig genes is dynamically regulated during B cell differentiation and is modulated by pre-B cell receptor signaling. J. Immunol. 182, 1362–1369 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. Aiba, Y., Kameyama, M., Yamazaki, T., Tedder, T. F. & Kurosaki, T. Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase. Blood 111, 1497–1503 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B. I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 335–344 (2004).

    Article  Google Scholar 

  144. Park, S. Y. et al. Focal adhesion kinase regulates the localization and retention of pro-B cells in bone marrow microenvironments. J. Immunol. 190, 1094–1102 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Fleming, H. E. & Paige, C. J. Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway. Immunity 15, 521–531 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Vosshenrich, C. A., Cumano, A., Muller, W., Di Santo, J. P. & Vieira, P. Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proc. Natl Acad. Sci. USA 101, 11070–11075 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Llorian, M., Stamataki, Z., Hill, S., Turner, M. S. & Martensson, I. L. The PI3K p110δ is required for down-regulation of RAG expression in immature B cells. J. Immunol. 178, 1981–1985 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Schram, B. R. et al. B cell receptor basal signaling regulates antigen-induced Ig light chain rearrangements. J. Immunol. 180, 4728–4741 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Tze, L. E. et al. Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. PLoS Biol. 3, e82 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Nemazee, D. & Weigert, M. Revising B cell receptors. J. Exp. Med. 191, 1813–1817 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Casellas, R. et al. Contribution of receptor editing to the antibody repertoire. Science 291, 1541–1544 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Casellas, R. et al. Igκ allelic inclusion is a consequence of receptor editing. J. Exp. Med. 204, 153–160 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Buckley, R. H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu. Rev. Immunol. 22, 625–655 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Marcus R. Clark or Harinder Singh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Flippase

Transporter protein that flips phospholipids from the outer membrane leaflet to the cytosolic leaflet of plasma and endosomal membranes.

Recombination-activating gene 1

(RAG1). RAG1 and RAG2 encode proteins that are involved in creating the DNA double-strand breaks that are necessary for producing the rearranged gene segments that encode the complete protein chains of T cell and B cell receptors.

Autophagy

The catabolic process in which the cell degrades its own components through the lysosomal pathway.

Recombination machinery

The molecular components that mediate immunoglobulin gene recombination. They include lymphoid-specific proteins, such as the recombination-activating gene (RAG) proteins and terminal deoxynucleotidyl transferase (TdT), and non-lymphoid restricted proteins that are involved in non-homologous DNA end-joining, including the DNA-dependent protein kinase subunits Ku70 (also known as XRCC6), Ku80 (also known as XRCC5) and DNA-PKcs (DNA-dependent protein kinase catalytic subunit), as well as Artemis and DNA ligase 4.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, M., Mandal, M., Ochiai, K. et al. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol 14, 69–80 (2014). https://doi.org/10.1038/nri3570

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3570

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing