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:

Control of lymphocyte development by nuclear factor-κB

Nature Reviews Immunology volume 5, pages 435–445 (2005)Cite this article

Key Points

  • In addition to its well-known role in driving the rapid host response to stress and pathogens, nuclear factor-κB (NF-κB) has a crucial role in T- and B-cell development. Its main (although not sole) role is to ensure lymphocyte survival at various developmental stages.

  • In early lymphopoiesis, NF-κB is probably needed to protect precursors from cell death induced by high levels of tumour-necrosis factor. At later stages, signalling through the pre-T-cell receptor and the pre-B-cell receptor (pre-BCR) activates NF-κB, which provides survival signals for developmental progression.

  • In the thymus, self-antigen-induced NF-κB activity might help to set the threshold for signals during positive and negative selection.

  • In the bone marrow, self-antigen-induced signalling through the BCR might induce apoptosis of immature B cells, owing to limited NF-κB activation.

  • NF-κB is essential for survival and maturation of transitional B cells in the spleen. Induction of the non-classical pathway of NF-κB activation through the B-cell-activating-factor receptor (BAFFR), which results in p52–REL-B induction, has a crucial role in these processes.

  • NF-κB is required for the long-term maintenance of mature T and B cells.

  • Generation of marginal-zone B cells requires extensive activation of NF-κB (which is possibly mediated through the BCR and BAFFR).

  • Activation of NF-κB mediated by IKK-β (inhibitor of NF-κB (IκB) kinase-β) is essential for the development of regulatory T-cell and natural killer T-cell subsets.

  • The normal function of NF-κB is perturbed in numerous diseases, leading, for example, to survival of self-reactive lymphocytes and autoimmune disease or to cancerous cells.

Abstract

The evolutionarily conserved nuclear factor-κB family of transcription factors is known to have a crucial role in rapid responses to stress and pathogens, inducing transcription of many genes that are essential for host defence. Now, studies of mice that are deficient in nuclear factor-κB-family members (or deficient in the activation of these factors) reveal that nuclear factor-κB is extensively involved in the development of T cells and B cells. And, as we review here, although these factors have several roles, their primary cell-autonomous function is to ensure lymphocyte survival at various developmental stages. This function is subverted in numerous diseases and can lead, for example, to survival of self-reactive lymphocytes or tumour cells.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: The NF-κB and IκB families.
Figure 2: Signal-transduction pathways for NF-κB activation.
Figure 3: Role of NF-κB in T-cell development.
Figure 4: Role of NF-κB in B-cell development.

Similar content being viewed by others

References

  1. Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002).

    Article  CAS  Google Scholar 

  2. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Hayden, M. S. & Ghosh, S. Signaling to NF-κB. Genes Dev. 18, 2195–2224 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Li, Z. -W., Rickert, R. C. & Karin, M. Genetic dissection of antigen receptor induced-NF-κB activation. Mol. Immunol. 41, 701–714 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Tam, W. F., Lee, L. H., Davis, L. & Sen, R. Cytoplasmic sequestration of Rel proteins by IκBα requires CRM1-dependent nuclear export. Mol. Cell. Biol. 20, 2269–2284 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee, S. -H. & Hannink, M. The N-terminal nuclear export sequence of IκBα is required for RanGTP-dependent binding to CRM1. J. Biol. Chem. 276, 23599–23606 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Horwitz, B. H., Scott, M. L., Cherry, S. R., Bronson, R. T. & Baltimore, D. Failure of lymphopoiesis after adoptive transfer of NF-κB-deficient fetal liver cells. Immunity 6, 765–772 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Senftleben, U., Li, Z. W., Baud, V. & Karin, M. IKKβ is essential for protecting T cells from TNFα-induced apoptosis. Immunity 14, 217–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Grossmann, M. et al. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc. Natl Acad. Sci. USA 96, 11848–11853 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Grossmann, M. et al. The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J. 19, 6351–6360 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmidt-Supprian, M. et al. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell 5, 981–989 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Makris, C. et al. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5, 969–979 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Smahi, A. et al. The NF-κB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum. Mol. Genet. 11, 2371–2375 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Germain, R. N. T-cell development and the CD4–CD8 lineage decision. Nature Rev. Immunol. 2, 309–322 (2002).

    Article  CAS  Google Scholar 

  16. Sen, J. et al. Expression and induction of nuclear factor-κB-related proteins in thymocytes. J. Immunol. 154, 3213–3221 (1995).

    CAS  PubMed  Google Scholar 

  17. Voll, R. E. et al. NF-κB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13, 677–689 (2000). Pre-TCR signals that activate NF-κB provide a survival signal for thymocytes.

    Article  CAS  PubMed  Google Scholar 

  18. Hardy, R. R. & Hayakawa, K. B cell development pathways. Annu. Rev. Immunol. 19, 595–562 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Feng, B., Cheng, S., Pear, W. S. & Liou, H. C. NF-κB inhibitor blocks B cell development at two checkpoints. Med. Immunol. 3, 1 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Middendorp, S., Dingjan, G. M. & Hendriks, R. W. Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice. J. Immunol. 168, 2695–2703 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Conley, M. E., Rohrer, J., Rapalus, L., Boylin, E. C. & Minegishi, Y. Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol. Rev. 178, 75–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Saijo, K. et al. Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development. Nature Immunol. 4, 274–279 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Xu, Y., Davidson, L., Alt, F. W. & Baltimore, D. Deletion of the Igκ light chain intronic enhancer/matrix attachment region impairs but does not abolish VκJκ rearrangement. Immunity 4, 377–385 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Kirillov, A. et al. A role of nuclear NF-κB in B-cell-specific demethylation of the Igκ locus. Nature Genet. 13, 435–441 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Mostoslavsky, R. et al. Demethylation and the establishment of κ allelic exclusion. Cold Spring Harb. Symp. Quant. Biol. 64, 197–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Goldmit, M. & Bergman, Y. Monoallelic gene expression: a repertoire of recurrent themes. Immunol. Rev. 200, 197–214 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Muljo, S. A. & Schlissel, M. S. A small molecule Abl kinase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines. Nature Immunol. 4, 31–37 (2003).

    Article  CAS  Google Scholar 

  29. Bendall, H. H., Sikes, M. L. & Oltz, E. M. Transcription factor NF-κB regulates Igλ light chain gene rearrangement. J. Immunol. 167, 264–269 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Scherer, D. C. et al. Corepression of RelA and c-Rel inhibits immunoglobulin κ gene transcription and rearrangement in precursor B lymphocytes. Immunity 5, 563–574 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Bendall, H. H., Sikes, M. L., Ballard, D. W. & Oltz, E. M. An intact NF-κB signaling pathway is required for maintenance of mature B cell subsets. Mol. Immunol. 36, 187–195 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Inlay, M. A., Tian, H., Lin, T. & Xu, Y. Important roles for E protein binding sites within the immunoglobulin κ chain intronic enhancer in activating VκJκ rearrangement. J. Exp. Med. 200, 1205–1211 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hettmann, T., DiDonato, J., Karin, M. & Leiden, J. M. An essential role for nuclear factor κB in promoting double positive thymocyte apoptosis. J. Exp. Med. 189, 145–158 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ren, H., Schmalstieg, A., van Oers, N. S. & Gaynor, R. B. I-κB kinases α and β have distinct roles in regulating murine T cell function. J. Immunol. 168, 3721–3731 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Kim, D., Peng, X. C. & Sun, X. H. Massive apoptosis of thymocytes in T-cell-deficient Id1 transgenic mice. Mol. Cell. Biol. 19, 8240–8253 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim, D. et al. Helix–loop–helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-κB activities. Immunity 16, 9–21 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Mora, A. L., Stanley, S., Armistead, W., Chan, A. C. & Boothby, M. Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-κB/Rel. J. Immunol. 167, 5628–5635 (2001). IκB super-repressor-mediated inhibition of NF-κB interferes with both negative and positive selection of thymocytes in vivo.

    Article  CAS  PubMed  Google Scholar 

  38. Fiorini, E. et al. Peptide-induced negative selection of thymocytes activates transcription of an NF-κB inhibitor. Mol. Cell 9, 637–648 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Guerin, S. et al. RelB reduces thymocyte apoptosis and regulates terminal thymocyte maturation. Eur. J. Immunol. 32, 1–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Schmidt-Supprian, M. et al. Mature T cells depend on signaling through the IKK complex. Immunity 19, 377–389 (2003). IKK and the classical pathway of NF-κB activation are essential for the generation and survival of mature T cells. The development of regulatory and memory T cells specifically depends on IKK-β.

    Article  CAS  PubMed  Google Scholar 

  41. Schmidt-Supprian, M. et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proc. Natl Acad. Sci. USA 101, 4566–4571 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Esslinger, C. W., Wilson, A., Sordat, B., Beermann, F. & Jongeneel, C. V. Abnormal T lymphocyte development induced by targeted overexpression of IκBα. J. Immunol. 158, 5075–5078 (1997).

    CAS  PubMed  Google Scholar 

  43. Boothby, M. R., Mora, A. L., Scherer, D. C., Brockman, J. A. & Ballard, D. W. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-κB. J. Exp. Med. 185, 1897–1907 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Attar, R. M., Macdonald-Bravo, H., Raventos-Suarez, C., Durham, S. K. & Bravo, R. Expression of constitutively active IκBβ in T cells of transgenic mice: persistent NF-κB activity is required for T-cell immune responses. Mol. Cell. Biol. 18, 477–487 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zheng, Y., Vig, M., Lyons, J., Van Parijs, L. & Beg, A. A. Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor κB in regulating mature T cell survival and in vivo function. J. Exp. Med. 197, 861–874 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sivakumar, V., Hammond, K. J., Howells, N., Pfeffer, K. & Weih, F. Differential requirement for Rel/nuclear factor κB family members in natural killer T cell development. J. Exp. Med. 197, 1613–1621 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. King, L. B. & Monroe, J. G. Immunobiology of the immature B cell: plasticity in the B-cell antigen receptor-induced response fine tunes negative selection. Immunol. Rev. 176, 86–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Wu, M. et al. Inhibition of NF-κB/Rel induces apoptosis of murine B cells. EMBO J. 15, 4682–4690 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Banerji, L. et al. BCR signals target p27 (Kip1) and cyclin D2 via the PI3-K signalling pathway to mediate cell cycle arrest and apoptosis of WEHI 231 B cells. Oncogene 20, 7352–7367 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Donjerkovic, D. & Scott, D. W. Activation-induced death in B lymphocytes. Cell Res. 10, 179–192 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Saijo, K. et al. Protein kinase C β controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase α. J. Exp. Med. 195, 1647–1652 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Guo, B., Su, T. T. & Rawlings, D. J. Protein kinase C family functions in B-cell activation. Curr. Opin. Immunol. 16, 367–373 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Su, T. T. et al. PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling. Nature Immunol. 3, 780–786 (2002).

    Article  CAS  Google Scholar 

  54. Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nature Rev. Immunol. 4, 348–359 (2004).

    Article  CAS  Google Scholar 

  55. Cancro, M. P. Peripheral B-cell maturation: the intersection of selection and homeostasis. Immunol. Rev. 197, 89–101 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Rathmell, J. C. B cell homeostasis: digital survival or analog growth? Immunol. Rev. 197, 116–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Franzoso, G. et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 11, 3482–3496 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gerondakis, S. & Strasser, A. The role of Rel/NF-κB transcription in B lymphocyte survival. Semin. Immunol. 15, 159–166 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Claudio, E., Brown, K., Park, S., Wang, H. & Siebenlist, U. BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nature Immunol. 3, 958–965 (2002). BAFFR activates the non-classical pathway of NF-κB activation, which is important for the survival and maturation of transitional B cells.

    Article  CAS  Google Scholar 

  60. Mackay, F. & Browning, J. L. BAFF: a fundamental survival factor for B cells. Nature Rev. Immunol. 2, 465–475 (2002).

    Article  CAS  Google Scholar 

  61. Gross, J. A. et al. TACI–Ig neutralizes molecules critical for B cell development and autoimmune disease: impaired B cell maturation in mice lacking BLyS. Immunity 15, 289–302 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Sasaki, Y., Casola, S., Kutok, J. L., Rajewsky, K. & Schmidt-Supprian, M. TNF family member B cell-activating factor (BAFF) receptor-dependent roles for BAFF in B cell physiology. J. Immunol. 173, 2245–2252 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Shulga-Morskaya, S. et al. B cell activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation. J. Immunol. 173, 2331–2341 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Tardivel, A. et al. The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF. Eur. J. Immunol. 34, 509–518 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Hsu, B. L., Harless, S. M., Lindsley, R. C., Hilbert, D. M. & Cancro, M. P. BlyS enables survival of transitional and mature B cells through distinct mediators. J. Immunol. 168, 5993–5996 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Mecklenbrauler, I., Kalled, S. L., Leitges, M., Mackay, F. & Tarakhovsky, A. Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signaling. Nature 431, 456–461 (2004). Spontaneous death of resting B cells is controlled by nuclear localization of PKC-δ. Treatment of cells with BAFF prevents the nuclear accumulation of PKC-δ.

    Article  CAS  Google Scholar 

  67. Senftleben, U. et al. Activation by IKKα of a second, evolutionarily conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001). IKK-α is a component of the non-classical pathway of NF-κB activation. This pathway leads to the processing of p100 into p52 rather than IκB degradation.

    Article  CAS  PubMed  Google Scholar 

  68. Kaisho, T. et al. IκB kinase α is essential for mature B cell development and function. J. Exp. Med. 193, 417–426 (2001). IKK-α-chimeric mice have disrupted B-cell zones in the spleen, and IKK-α-deficient B cells have impaired survival and mitogenic responses in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yamada, T. et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-κB-inducing kinase. J. Immunol. 165, 804–812 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Pasparakis, M., Schmidt-Supprian, M. & Rajewsky, K. IκB kinase signaling is essential for maintenance of mature B cells. J. Exp. Med. 196, 743–752 (2002). Conditional knockout of Ikk-β or Ikk-γ from B cells reveals the importance of the classical pathway of NF-κB activation for maintenance of peripheral B cells, beginning with defects in transitional B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Khan, W. N. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol. Res. 23, 147–156 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Cariappa, A., Liou, H. C., Horwitz, B. H. & Pillai, S. Nuclear factor κB is required for the development of marginal zone B lymphocytes. J. Exp. Med. 192, 1175–1182 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Weih, D. S., Yilmaz, Z. B. & Weih, F. Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J. Immunol. 167, 1909–1919 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Grumont, R. J. et al. B lymphocytes differentially use the Rel and nuclear factor κB1 (NF-κB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J. Exp. Med. 187, 663–674 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Prendes, M., Zheng, Y. & Beg, A. A. Regulation of developing B cell survival by RelA-containing NF-κB complexes. J. Immunol. 171, 3963–3969 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Kraus, M., Alimzhanov, M. B., Rajewsky, N. & Rajewsky, K. Survival of resting mature B lymphocytes depends on BCR signaling via the Igα/β heterodimer. Cell 117, 787–800 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Xue, L. et al. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nature Immunol. 4, 857–864 (2003). BCL-10-deficient mice show impaired progression of transitional B cells to mature B cells, as well as a decrease in the number of marginal-zone B cells and B1 cells. BCL-10-deficient follicular and marginal-zone B cells also fail to proliferate. So, BCL-10 is essential for the development of all mature B-cell subsets.

    Article  CAS  Google Scholar 

  78. Li, Z. -W., Omori, S. A., Labuda, T., Karin, M. & Rickert, R. C. IKKβ is required for peripheral B cell survival and proliferation. J. Immunol. 170, 4630–4637 (2003). Loss of IKK-β from B cells severely reduces the number of cells in all peripheral B-cell subsets. IKK-β-deficient B cells have impaired responses, indicating that there is a role for this protein in the activation and maintenance of B cells.

    Article  CAS  PubMed  Google Scholar 

  79. Pohl, T. et al. The combined absence of NF-κB1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc. Natl Acad. Sci. USA 99, 4514–4519 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kayagaki, N. et al. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-κB2. Immunity 17, 515–524 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190, 1697–1710 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Khare, S. D. et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc. Natl Acad. Sci. USA 97, 3370–3375 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Davis, R. E., Brown, K. D., Siebenlist, U. & Staudt, L. M. Constitutive nuclear factor κB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells J. Exp. Med. 194, 1861–1874 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lam, L. T. et al. Small molecule inhibitors of IκB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin. Cancer Res. 11, 28–40 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Krappmann, D. et al. Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 18, 943–953 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Hinz, M. et al. Nuclear factor κB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J. Exp. Med. 196, 605–617 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members, past and present, of the Siebenlist laboratory for their contributions.

Author information

Authors and Affiliations

  1. Immune Activation Section, Laboratory of Immune Regulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892-1876, Maryland, USA

    Ulrich Siebenlist, Keith Brown & Estefania Claudio

Authors
  1. Ulrich Siebenlist
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keith Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Estefania Claudio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich Siebenlist.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

IκBα

IκBβ

IκBε

NF-κB1

NF-κB2

REL

REL-A

REL-B

Glossary

REL-HOMOLOGY DOMAIN

(RHD). A conserved domain of ∼300 amino acids that is found in the amino-terminal portion of nuclear factor-κB (NF-κB)-family members. It contains motifs that are responsible for dimerization, nuclear translocation and binding to NF-κB-binding motifs that are present in DNA.

TRANSACTIVATION DOMAINS

Diverse structural elements that are present in transcription factors and are responsible for the activation of gene promoters. They interact with the transcriptional apparatus of the cell.

PRE-BCR

(Pre-B-cell receptor). A receptor that is formed at the surface of pre-B cells by the pairing of rearranged immunoglobulin heavy chains with surrogate immunoglobulin light chains; it is associated with the signalling heterodimer of Igα and Igβ. Signalling by the pre-BCR possibly occurs in the absence of known ligands and is a crucial event in B-cell development.

GRANULOPOIESIS

The formation of granulocytes in the bone marrow. It is controlled by several cytokines, including granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage CSF (GM-CSF).

RANDOM LYONIZATION

The random inactivation of all but one X chromosome in most cells.

IκB SUPER-REPRESSOR

A mutant form of the nuclear factor-κB (NF-κB) inhibitor IκBα. This form cannot be phosphorylated and degraded in response to signals, so it functions as a super-repressor of NF-κB, blocking its activation by upstream signals.

DEMETHYLATION

The removal of methyl groups from DNA. During rearrangement at immunoglobulin heavy-chain loci, only demethylated genomic loci are rearranged.

HELIX–LOOP–HELIX PROTEINS

(HLH proteins). Proteins that contain a particular domain (the HLH domain) that mediates dimerization between family members. This domain consists of a 40–50 amino-acid sequence that can form two amphipathic helices joined by a loop. Many transcription factors and regulatory proteins contain an HLH domain.

RADIATION CHIMERAS

Animals that contain cell populations of different genotypes as a result of the transfer of haematopoietic stem cells from fetal liver or bone marrow to a recipient in which haematopoietic cell populations (and other actively dividing cell populations) have been fully or partially destroyed by lethal or sub-lethal ionizing radiation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Siebenlist, U., Brown, K. & Claudio, E. Control of lymphocyte development by nuclear factor-κB. Nat Rev Immunol 5, 435–445 (2005). https://doi.org/10.1038/nri1629

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1629

This article is cited by

Search

Advanced 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