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
  • Published:

The complicated role of NF-κB in T-cell selection

Cellular & Molecular Immunology volume 7, pages 89–93 (2010)Cite this article

Abstract

The nuclear factor (NF)-κB transcription factor family plays important roles in the immune system. Aberrant NF-κB signaling is frequently associated with inflammation and autoimmune diseases but the underlying mechanisms are not fully understood. Recent studies show that NF-κB plays a critical role in T-cell central tolerance. Two NF-κB signaling pathways have been identified: the canonical pathway and the alternative pathway. In the establishment of T-cell central tolerance, the alternative pathway appears to be the key signaling component in thymic stromal cells for their development and function, while the canonical pathway exerts its function more in autonomous T-cell selection. This review intends to summarize the current understanding of the role of NF-κB in establishing T-cell central tolerance and highlight unsolved intriguing questions for future work.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Sen R, Baltimore D . Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986; 46: 705–716.

    Article  CAS  PubMed  Google Scholar 

  2. Hoffmann A, Baltimore D . Circuitry of nuclear factor kappaB signaling. Immunol Rev 2006; 210: 171–186.

    Article  PubMed  Google Scholar 

  3. Xiao G, Harhaj EW, Sun SC . NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7: 401–409.

    Article  CAS  PubMed  Google Scholar 

  4. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001; 293: 1495–1499.

    Article  CAS  PubMed  Google Scholar 

  5. Weih F, Caamano J . Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev 2003; 195: 91–105.

    Article  CAS  PubMed  Google Scholar 

  6. Basak S, Kim H, Kearns JD, Tergaonkar V, O’Dea E, Werner S et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell 2007; 128: 369–381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ishimaru N, Kishimoto H, Hayashi Y, Sprent J . Regulation of naive T cell function by the NF-kappaB2 pathway. Nat Immunol 2006; 7: 763–772.

    Article  CAS  PubMed  Google Scholar 

  8. Basak S, Shih VF, Hoffmann A . Generation and activation of multiple dimeric transcription factors within the NF-kappaB signaling system. Mol Cell Biol 2008; 28: 3139–3150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jacque E, Tchenio T, Piton G, Romeo PH, Baud V . RelA repression of RelB activity induces selective gene activation downstream of TNF receptors. Proc Natl Acad Sci USA 2005; 102: 14635–14640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Marienfeld R, May MJ, Berberich I, Serfling E, Ghosh S, Neumann M . RelB forms transcriptionally inactive complexes with RelA/p65. J Biol Chem 2003; 278: 19852–19860.

    Article  CAS  PubMed  Google Scholar 

  11. Xia Y, Chen S, Wang Y, Mackman N, Ku G, Lo D et al. RelB modulation of ikappa balpha stability as a mechanism of transcription suppression of interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in fibroblasts. Mol Cell Biol 1999; 19: 7688–7696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 1995; 373: 531–536.

    Article  CAS  PubMed  Google Scholar 

  13. Kajiura F, Sun S, Nomura T, Izumi K, Ueno T, Bando Y et al. NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 2004; 172: 2067–2075.

    Article  CAS  PubMed  Google Scholar 

  14. Kinoshita D, Hirota F, Kaisho T, Kasai M, Izumi K, Bando Y et al. Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J Immunol 2006; 176: 3995–4002.

    Article  CAS  PubMed  Google Scholar 

  15. Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 2005; 308: 248–251.

    Article  CAS  PubMed  Google Scholar 

  16. Zhu M, Chin RK, Christiansen PA, Lo JC, Liu X, Ware C et al. NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J Clin Invest 2006; 116: 2964–2971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang B, Wang Z, Ding J, Peterson P, Gunning WT, Ding HF . NF-kappaB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells. J Biol Chem 2006; 281: 38617–38624.

    Article  CAS  PubMed  Google Scholar 

  18. Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, Peterson P et al. Lymphotoxin pathway directs thymic Aire expression. Nat Immunol 2003; 4: 1121–1127.

    Article  CAS  PubMed  Google Scholar 

  19. Chin RK, Zhu M, Christiansen PA, Liu W, Ware C, Peltonen L et al. Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen. J Immunol 2006; 177: 290–297.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang X, Wang H, Claudio E, Brown K, Siebenlist U . A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance. Immunity 2007; 27: 438–452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley S et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 2002; 298: 1395–1401.

    Article  CAS  PubMed  Google Scholar 

  22. Hamazaki Y, Fujita H, Kobayashi T, Choi Y, Scott HS, Matsumoto M et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat Immunol 2007; 8: 304–311.

    Article  CAS  PubMed  Google Scholar 

  23. Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 2005; 202: 33–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Boehm T, Scheu S, Pfeffer K, Bleul CC . Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med 2003; 198: 757–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Milicevic NM, Nohroudi K, Milicevic Z, Westermann J . Activation of cortical and inhibited differentiation of medullary epithelial cells in the thymus of lymphotoxin-beta receptor-deficient mice: an ultrastructural study. J Anat 2008; 212: 114–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 2008; 29: 438–450.

    Article  CAS  PubMed  Google Scholar 

  27. Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 2008; 29: 423–437.

    Article  CAS  PubMed  Google Scholar 

  28. Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville S et al. RANK signals from CD4+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med 2007; 204: 1267–1272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown K et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 1997; 11: 3482–3496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kyewski B, Klein L . A central role for central tolerance. Annu Rev Immunol 2006; 24: 571–606.

    Article  CAS  PubMed  Google Scholar 

  31. Murumagi A, Vahamurto P, Peterson P . Characterization of regulatory elements and methylation pattern of the autoimmune regulator (AIRE) promoter. J Biol Chem 2003; 278: 19784–19790.

    Article  PubMed  Google Scholar 

  32. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY . Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 2005; 22: 329–341.

    Article  CAS  PubMed  Google Scholar 

  33. Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee L et al. Selection of Foxp3+; regulatory T cells specific for self antigen expressed and presented by Aire+; medullary thymic epithelial cells. Nat Immunol 2007; 8: 351–358.

    Article  CAS  PubMed  Google Scholar 

  34. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D . The cellular mechanism of Aire control of T cell tolerance. Immunity 2005; 23: 227–239.

    Article  CAS  PubMed  Google Scholar 

  35. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006; 212: 8–27.

    Article  CAS  PubMed  Google Scholar 

  36. Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM . Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med 2001; 194: 427–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kwan J, Killeen N . CCR7 directs the migration of thymocytes into the thymic medulla. J Immunol 2004; 172: 3999–4007.

    Article  CAS  PubMed  Google Scholar 

  38. Ueno T, Saito F, Gray DH, Kuse S, Hieshima K, Nakano H et al. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med 2004; 200: 493–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Campbell JJ, Pan J, Butcher EC . Cutting edge: developmental switches in chemokine responses during T cell maturation. J Immunol 1999; 163: 2353–2357.

    CAS  PubMed  Google Scholar 

  40. Misslitz A, Pabst O, Hintzen G, Ohl L, Kremmer E, Petrie H et al. Thymic T cell development and progenitor localization depend on CCR7. J Exp Med 2004; 200: 481–491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, Seach N et al. CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 2006; 24: 165–177.

    Article  CAS  PubMed  Google Scholar 

  42. Zhu M, Chin RK, Tumanov AV, Liu X, Fu YX . Lymphotoxin beta receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J Immunol 2007; 179: 8069–8075.

    Article  CAS  PubMed  Google Scholar 

  43. Drayton DL, Bonizzi G, Ying X, Liao S, Karin M, Ruddle NH . IkappaB kinase complex alpha kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue. J Immunol 2004; 173: 6161–6168.

    Article  CAS  PubMed  Google Scholar 

  44. Weih DS, Yilmaz ZB, Weih F . Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J Immunol 2001; 167: 1909–1919.

    Article  CAS  PubMed  Google Scholar 

  45. Lo JC, Chin RK, Lee Y, Kang HS, Wang Y, Weinstock J et al. Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues. J Clin Invest 2003; 112: 1495–1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Venanzi ES, Gray DH, Benoist C, Mathis D . Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol 2007; 179: 5693–5700.

    Article  CAS  PubMed  Google Scholar 

  47. Davalos-Misslitz ACM, Worbs T, Willenzon S, Bernhardt G, Forster R . Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice. Blood 2007; 110: 4351–4359.

    Article  CAS  PubMed  Google Scholar 

  48. Le Borgne M, Ladi E, Dzhagalov I, Herzmark P, Liao YF, Chakraborty A et al. The impact of negative selection on thymocyte migration in the medulla. Nat Immunol 2009; 10: 823–830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zheng Y, Vig M, Lyons J, van Parijs L, Beg AA . Combined deficiency of p50 and cRel in CD4+; T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med 2003; 197: 861–874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schmidt-Supprian M, Courtois G, Tian J, Coyle AJ, Israel A, Rajewsky K et al. Mature T cells depend on signaling through the IKK complex. Immunity 2003; 19: 377–389.

    Article  CAS  PubMed  Google Scholar 

  51. Mora AL, Stanley S, Armistead W, Chan AC, Boothby M . Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-kappaB/Rel. J Immunol 2001; 167: 5628–5635.

    Article  CAS  PubMed  Google Scholar 

  52. Fiorini E, Schmitz I, Marissen WE, Osborn SL, Touma M, Sasada T et al. Peptide-induced negative selection of thymocytes activates transcription of an NF-kappaB inhibitor. Mol Cell 2002; 9: 637–648.

    Article  CAS  PubMed  Google Scholar 

  53. Siebenlist U, Brown K, Claudio E . Control of lymphocyte development by nuclear factor-kappaB. Nat Rev Immunol 2005; 5: 435–445.

    Article  CAS  PubMed  Google Scholar 

  54. Bates PW, Miyamoto S . Expanded nuclear roles for IkappaBs. Sci STKE 2004; 2004: pe48.

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose original work is not cited here due to space limitation.

Author information

Authors and Affiliations

  1. CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China

    Mingzhao Zhu

  2. Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL, USA

    Yangxin Fu

Authors
  1. Mingzhao Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yangxin Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mingzhao Zhu or Yangxin Fu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, M., Fu, Y. The complicated role of NF-κB in T-cell selection. Cell Mol Immunol 7, 89–93 (2010). https://doi.org/10.1038/cmi.2009.112

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2009.112

Keywords

This article is cited by

Search

Advanced search

Quick links