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:

The non-canonical NF-κB pathway in immunity and inflammation

Nature Reviews Immunology volume 17, pages 545–558 (2017)Cite this article

Subjects

Key Points

  • NF-κB (nuclear factor-κB) activation is mediated by two main signalling pathways, the canonical and non-canonical pathways, which differ in both signalling mechanisms and biological functions.

  • The canonical NF-κB pathway is stimulated by ligands of diverse immune receptors and involves the rapid and transient activation of IκB kinase (IKK), IKK-mediated IκBα phosphorylation, and subsequent IκBα degradation and nuclear translocation of canonical NF-κB members, including p50, RELA and c-REL.

  • The non-canonical NF-κB pathway selectively responds to signals from a subset of tumour necrosis factor receptor (TNFR) superfamily members and involves slow and persistent activation of NF-κB-inducing kinase (NIK), NIK-mediated p100 phosphorylation, and subsequent p100 processing and nuclear translocation of non-canonical NF-κB members, including p52 and RELB.

  • The non-canonical NF-κB pathway is tightly controlled by ubiquitin-dependent degradation of NIK mediated by an E3 ubiquitin ligase complex composed of cIAP family members, TNFR-associated factor 2 (TRAF2) and TRAF3; activation of non-canonical NF-κB involves signal-induced disruption of the cIAP E3 complex, typically via degradation of TRAF3, and accumulation of NIK.

  • The non-canonical NF-κB pathway regulates important aspects of immune functions, including lymphoid organ development, the cross-priming function of dendritic cells, B cell survival and germinal centre reactions, generation and maintenance of effector and memory T cells, and antiviral innate immunity.

  • The non-canonical NF-κB pathway is involved in various inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, kidney inflammation and injury, metabolic inflammation, and central nervous system inflammation.

Abstract

The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.

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

Figure 1: Canonical and non-canonical NF-κB pathways.
Figure 2: Regulation and activation of the non-canonical NF-κB pathway.
Figure 3: The non-canonical NF-κB pathway regulates GC reactions in multiple steps.
Figure 4: Regulation of T cell responses by canonical and non-canonical NF-κB pathways.
Figure 5: The non-canonical NF-κB pathway regulates inflammation in different cell types.

Similar content being viewed by others

References

  1. Hayden, M. S. & Ghosh, S. Shared principles in NF-κB signaling. Cell 132, 344–362 (2008).

    CAS  PubMed  Google Scholar 

  2. Sun, S. C. & Ley, S. C. New insights into NF-κB regulation and function. Trends Immunol. 29, 469–478 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lin, L., DeMartino, G. N. & Greene, W. C. Cotranslational biogenesis of NF-κB p50 by the 26S proteasome. Cell 92, 819–828 (1998).

    CAS  PubMed  Google Scholar 

  4. Sun, S. C. The noncanonical NF-κB pathway. Immunol. Rev. 246, 125–140 (2012).

    PubMed  PubMed Central  Google Scholar 

  5. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

    CAS  PubMed  Google Scholar 

  6. Hu, H. & Sun, S. C. Ubiquitin signaling in immune responses. Cell Res. 26, 457–483 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang, H. T. et al. Coordinate regulation of TPL-2 and NF-κB signaling in macrophages by NF-κB1 p105. Mol. Cell. Biol. 32, 3438–3451 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sriskantharajah, S. et al. Proteolysis of NF-κB1 p105 is essential for T cell antigen receptor-induced proliferation. Nat. Immunol. 10, 38–47 (2009).

    CAS  PubMed  Google Scholar 

  9. Israel, A. The IKK complex, a central regulator of NF-κB activation. Cold Spring Harb. Perspect. Biol. 2, a000158 (2010).

    PubMed  PubMed Central  Google Scholar 

  10. Xiao, G., Harhaj, E. W. & Sun, S. C. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401–409 (2001). This is the first paper to report inducible processing of p100 and to identify NIK as an inducing kinase.

    CAS  PubMed  Google Scholar 

  11. Fong, A. & Sun, S.-C. Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-κB2/p100. J. Biol. Chem. 277, 22111–22114 (2002).

    CAS  PubMed  Google Scholar 

  12. Liang, C., Zhang, M. & Sun, S. C. β-TrCP binding and processing of NF-κB2/p100 involve its phosphorylation at serines 866 and 870. Cell. Signal. 18, 1309–1317 (2006).

    CAS  PubMed  Google Scholar 

  13. Senftleben, U. et al. Activation of IKKa of a second, evolutionary conserved, NF-kB signaling pathway. Science 293, 1495–1499 (2001). This paper identifies IKK α as a NIK-target kinase that directly phosphorylates p100 to induce p100 processing.

    CAS  PubMed  Google Scholar 

  14. Jin, W., Zhou, X. F., Yu, J., Cheng, X. & Sun, S. C. Regulation of Th17 cell differentiation and EAE induction by the MAP3K NIK. Blood 113, 6603–6610 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Boutaffala, L. et al. NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis. Cell Death Differ. 22, 2020–2033 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hacker, H., Chi, L., Rehg, J. E. & Redecke, V. NIK prevents the development of hypereosinophilic syndrome-like disease in mice independent of IKKalpha activation. J. Immunol. 188, 4602–4610 (2012).

    PubMed  Google Scholar 

  17. Sun, S. C. Non-canonical NF-κB signaling pathway. Cell Res. 21, 71–85 (2011).

    CAS  PubMed  Google Scholar 

  18. Liu, F., Xia, Y., Parker, A. S. & Verma, I. M. IKK biology. Immunol. Rev. 246, 239–253 (2012).

    PubMed  PubMed Central  Google Scholar 

  19. Liu, B. et al. IKKalpha is required to maintain skin homeostasis and prevent skin cancer. Cancer Cell 14, 212–225 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Xiao, Z. et al. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 23, 527–540 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Xiao, G., Fong, A. & Sun, S. C. Induction of p100 processing by NF-κB-inducing kinase involves docking IκB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J. Biol. Chem. 279, 30099–30105 (2004).

    CAS  PubMed  Google Scholar 

  22. Sun, S.-C., Ganchi, P. A., Beraud, C., Ballard, D. W. & Greene, W. C. Autoregulation of the NF-kB transactivator Rel A (p65) by multiple cytoplasmic inhibitors containing ankyrin motifs. Proc. Natl Acad. Sci. USA 91, 1346–1350 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tucker, E. et al. A novel mutation in the Nfkb2 gene generates an NF-κ B2 “super repressor”. J. Immunol. 179, 7514–7522 (2007).

    CAS  PubMed  Google Scholar 

  24. Zarnegar, B., Yamazaki, S., He, J. Q. & Cheng, G. Control of canonical NF-κB activation through the NIK-IKK complex pathway. Proc. Natl Acad. Sci. USA 105, 3503–3508 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu, J. et al. T cell-intrinsic function of the noncanonical NF-κB pathway in the regulation of GM-CSF expression and experimental autoimmune encephalomyelitis pathogenesis. J. Immunol. 193, 422–430 (2014).

    CAS  PubMed  Google Scholar 

  26. De Silva, N. S., Silva, K., Anderson, M. M., Bhagat, G. & Klein, U. Impairment of mature B cell maintenance upon combined deletion of the alternative NF-κB transcription factors RELB and NF-κB2 in B cells. J. Immunol. 196, 2591–2601 (2016).

    CAS  PubMed  Google Scholar 

  27. Shih, V. F. et al. Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways. Nat. Immunol. 13, 1162–1170 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shinkura, R. et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κB-inducing kinase. Nat. Genet. 22, 74–77 (1999).

    CAS  PubMed  Google Scholar 

  29. Dejardin, E. et al. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525–535 (2002).

    CAS  PubMed  Google Scholar 

  30. Claudio, E., Brown, K., Park, S., Wang, H. & Siebenlist, U. BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nat. Immunol. 3, 958–965 (2002).

    CAS  PubMed  Google Scholar 

  31. Coope, H. J. et al. CD40 regulates the processing of NF-κB2 p100 to p52. EMBO J. 15, 5375–5385 (2002).

    Google Scholar 

  32. 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). References 29–32 are the first papers to report ligand-induced non-canonical NF-κB activation.

    CAS  PubMed  Google Scholar 

  33. Saitoh, T. et al. TWEAK induces NF-κB2 p100 processing and long lasting NF-κB activation. J. Biol. Chem. 278, 36005–36012 (2003).

    CAS  PubMed  Google Scholar 

  34. Ramakrishnan, P., Wang, W. & Wallach, D. Receptor-specific signaling for both the alternative and the canonical NF-κB activation pathways by NF-κB-inducing kinase. Immunity 21, 477–489 (2004).

    CAS  PubMed  Google Scholar 

  35. Nishikori, M., Ohno, H., Haga, H. & Uchiyama, T. Stimulation of CD30 in anaplastic large cell lymphoma leads to production of nuclear factor-κB p52, which is associated with hyperphosphorylated Bcl-3. Cancer Sci. 96, 487–497 (2005).

    CAS  PubMed  Google Scholar 

  36. Nonaka, M. et al. Aberrant NF-κB2/p52 expression in Hodgkin/Reed-Sternberg cells and CD30-transformed rat fibroblasts. Oncogene 24, 3976–3986 (2005).

    CAS  PubMed  Google Scholar 

  37. Novack, D. V. et al. The IκB function of NF-κB2 p100 controls stimulated osteoclastogenesis. J. Exp. Med. 198, 771–781 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Murray, S. E. et al. NF-κB-inducing kinase plays an essential T cell-intrinsic role in graft-versus-host disease and lethal autoimmunity in mice. J. Clin. Invest. 121, 4775–4786 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. McPherson, A. J., Snell, L. M., Mak, T. W. & Watts, T. H. Opposing roles for TRAF1 in the alternative versus classical NF-κB pathway in T cells. J. Biol. Chem. 287, 23010–23019 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Jin, J. et al. Noncanonical NF-κB pathway controls the production of type I interferons in antiviral innate immunity. Immunity 40, 342–354 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Croft, M. The role of TNF superfamily members in T-cell function and diseases. Nat. Rev. Immunol. 9, 271–285 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Xiao, X. et al. OX40 signaling favors the induction of TH9 cells and airway inflammation. Nat. Immunol. 13, 981–990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu, P., Li, K., Garofalo, R. P. & Brasier, A. R. Respiratory syncytial virus induces RelA release from cytoplasmic 100-kDa NF-κ B2 complexes via a novel retinoic acid-inducible gene-I·NF-κB-inducing kinase signaling pathway. J. Biol. Chem. 283, 23169–23178 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Manches, O., Fernandez, M. V., Plumas, J., Chaperot, L. & Bhardwaj, N. Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype. Proc. Natl Acad. Sci. USA 109, 14122–14127 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ruckle, A. et al. The NS1 protein of influenza A virus blocks RIG-I-mediated activation of the noncanonical NF-κB pathway and p52/RelB-dependent gene expression in lung epithelial cells. J. Virol. 86, 10211–10217 (2012).

    PubMed  PubMed Central  Google Scholar 

  46. Xiao, G. et al. Retroviral oncoprotein Tax induces processing of NF-κB2/p100 in T cells: evidence for the involvement of IKKalpha. EMBO J. 20, 6805–6815 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Luftig, M. et al. Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-κB activation. Proc. Natl Acad. Sci. USA 101, 141–146 (2004).

    CAS  PubMed  Google Scholar 

  48. Matta, H. & Chaudhary, P. M. Activation of alternative NF-κ B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc. Natl Acad. Sci. USA 101, 9399–9404 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Cho, I. R. et al. Activation of non-canonical NF-κB pathway mediated by STP-A11, an oncoprotein of Herpesvirus saimiri. Virology 359, 37–45 (2007).

    CAS  PubMed  Google Scholar 

  50. de Jong, S. J. et al. Noncanonical NF-κB activation by the oncoprotein Tio occurs through a nonconserved TRAF3-binding motif. Sci. Signal. 6, ra27 (2013).

    PubMed  Google Scholar 

  51. Ohmae, T. et al. Helicobacter pylori activates NF-κB via the alternative pathway in B lymphocytes. J. Immunol. 175, 7162–7169 (2005).

    CAS  PubMed  Google Scholar 

  52. Ge, J. et al. A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors. Proc. Natl Acad. Sci. USA 106, 13725–13730 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Liao, G., Zhang, M., Harhaj, E. W. & Sun, S. C. Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 279, 26243–26250 (2004). This paper demonstrates that NIK is regulated by TRAF3-dependent proteolysis and activated via signal-induced TRAF3 degradation.

    CAS  PubMed  Google Scholar 

  54. He, J. Q. et al. Rescue of TRAF3-null mice by p100 NF-κ B deficiency. J. Exp. Med. 203, 2413–2418 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sasaki, Y. et al. NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells. Proc. Natl Acad. Sci. USA 105, 10883–10888 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. de Leon-Boenig, G. et al. The crystal structure of the catalytic domain of the NF-κB inducing kinase reveals a narrow but flexible active site. Structure 20, 1704–1714 (2012).

    CAS  PubMed  Google Scholar 

  57. Liu, J. et al. Structure of the nuclear factor κB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation. J. Biol. Chem. 287, 27326–27334 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nat. Immunol. 9, 1364–1370 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zarnegar, B. J. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 9, 1371–1378 (2008). References 58 and 59 propose a model whereby TRAF3 functions as a cIAP–TRAF2–TRAF3 complex to mediate NIK ubiquitylation.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Gardam, S., Sierro, F., Basten, A., Mackay, F. & Brink, R. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity 28, 391–401 (2008).

    CAS  PubMed  Google Scholar 

  61. Grech, A. P. et al. TRAF2 differentially regulates the canonical and noncanonical pathways of NF-κB activation in mature B cells. Immunity 21, 629–642 (2004).

    CAS  PubMed  Google Scholar 

  62. Xie, P., Stunz, L. L., Larison, K. D., Yang, B. & Bishop, G. A. Tumor necrosis factor receptor-associated factor 3 is a critical regulator of B cell homeostasis in secondary lymphoid organs. Immunity 27, 253–267 (2007).

    PubMed  PubMed Central  Google Scholar 

  63. Gardam, S. et al. Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. Blood 117, 4041–4051 (2011).

    CAS  PubMed  Google Scholar 

  64. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFalpha-dependent apoptosis. Cell 131, 669–681 (2007).

    CAS  PubMed  Google Scholar 

  65. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131, 682–693 (2007). References 64 and 65 demonstrated the involvement of cIAP in the negative regulation of non-canonical NF-κB pathway.

    CAS  PubMed  Google Scholar 

  66. Allen, I. C. et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. Immunity 36, 742–754 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lich, J. D. et al. Monarch-1 suppresses non-canonical NF-κB activation and p52-dependent chemokine expression in monocytes. J. Immunol. 178, 1256–1260 (2007).

    CAS  PubMed  Google Scholar 

  68. Hu, H. et al. OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3. Nature 494, 371–374 (2013). This study identified the OTUD7B as a deubiquitinase of TRAF3 that controls non-canonical NF-κB signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Razani, B. et al. Negative feedback in non-canonical NF-κB signaling modulates NIK stability through IKKα-mediated phosphorylation. Sci. Signal. 3, ra41 (2010).

    PubMed  PubMed Central  Google Scholar 

  70. Jin, J. et al. The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling. Nat. Immunol. 13, 1101–1109 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Maminska, A. et al. ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors. Sci. Signal. 9, ra8 (2016).

    PubMed  Google Scholar 

  72. Morrison, M. D., Reiley, W., Zhang, M. & Sun, S. C. An atypical tumor necrosis factor (TNF) receptor-associated factor-binding motif of B cell-activating factor belonging to the TNF family (BAFF) receptor mediates induction of the noncanonical NF-κB signaling pathway. J. Biol. Chem. 280, 10018–10024 (2005).

    CAS  PubMed  Google Scholar 

  73. Sanjo, H., Zajonc, D. M., Braden, R., Norris, P. S. & Ware, C. F. Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor. J. Biol. Chem. 285, 17148–17155 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ganeff, C. et al. Induction of the alternative NF-κB pathway by lymphotoxin alphabeta (LTalphabeta) relies on internalization of LTbeta receptor. Mol. Cell. Biol. 31, 4319–4334 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Jane-wit, D. et al. Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes. Proc. Natl Acad. Sci. USA 112, 9686–9691 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Dejardin, E. The alternative NF-κB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem. Pharmacol. 72, 1161–1179 (2006).

    CAS  PubMed  Google Scholar 

  77. Novack, D. V. Role of NF-κB in the skeleton. Cell Res. 21, 169–182 (2011).

    CAS  PubMed  Google Scholar 

  78. Weih, F. & Caamaño, J. Regulation of secondary lymphoid organ development by the nuclear factor-κB signal transduction pathway. Immunol. Rev. 195, 91–105 (2003).

    CAS  PubMed  Google Scholar 

  79. Miyawaki, S. et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 24, 429–434 (1994).

    CAS  PubMed  Google Scholar 

  80. Matsushima, A. et al. Essential role of nuclear factor (NF)-κB-inducing kinase and inhibitor of κB (IκB) kinase alpha in NF-κB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 193, 631–636 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Yilmaz, Z. B., Weih, D. S., Sivakumar, V. & Weih, F. RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. EMBO J. 22, 121–130 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Carragher, D. et al. A stroma-derived defect in NF-κB2−/− mice causes impaired lymph node development and lymphocyte recruitment. J. Immunol. 173, 2271–2279 (2004).

    CAS  PubMed  Google Scholar 

  83. Lo, J. C. et al. Coordination between NF-κB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues. Blood 107, 1048–1055 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).

    CAS  PubMed  Google Scholar 

  85. Abramson, J. & Anderson, G. Thymic epithelial cells. Annu. Rev. Immunol. 35, 85–118 (2017).

    CAS  PubMed  Google Scholar 

  86. Akiyama, T. et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423–437 (2008).

    CAS  PubMed  Google Scholar 

  87. Burkly, L. et al. Expression of relB is required for the development of thymic medulla and dentritic cells. Nature 373, 531–536 (1995).

    CAS  PubMed  Google Scholar 

  88. Weih, F. et al. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κ B/Rel family. Cell 80, 331–340 (1995).

    CAS  PubMed  Google Scholar 

  89. Kajiura, F. et al. NF-κ B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J. Immunol. 172, 2067–2075 (2004).

    CAS  PubMed  Google Scholar 

  90. Kinoshita, D. et al. Essential role of IκB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J. Immunol. 176, 3995–4002 (2006).

    CAS  PubMed  Google Scholar 

  91. Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005).

    CAS  PubMed  Google Scholar 

  92. Onder, L. et al. Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction. Eur. J. Immunol. 45, 2218–2231 (2015).

    CAS  PubMed  Google Scholar 

  93. Baik, S., Sekai, M., Hamazaki, Y., Jenkinson, W. E. & Anderson, G. Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. Eur. J. Immunol. 46, 857–862 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhu, M. et al. NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J. Clin. Invest. 116, 2964–2971 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. LaFlam, T. N. et al. Identification of a novel cis-regulatory element essential for immune tolerance. J. Exp. Med. 212, 1993–2002 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Haljasorg, U. et al. A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice. Eur. J. Immunol. 45, 3246–3256 (2015).

    CAS  PubMed  Google Scholar 

  97. Steinman, R. M. & Hemmi, H. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 311, 17–58 (2006).

    CAS  PubMed  Google Scholar 

  98. Summers deLuca, L. & Gommerman, J. L. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat. Rev. Immunol. 12, 339–351 (2012).

    PubMed  Google Scholar 

  99. Gerondakis, S. et al. Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models. Oncogene 25, 6781–6799 (2006).

    CAS  PubMed  Google Scholar 

  100. Seki, T. et al. Visualization of RelB expression and activation at the single-cell level during dendritic cell maturation in Relb-Venus knock-in mice. J. Biochem. 158, 485–495 (2015).

    CAS  PubMed  Google Scholar 

  101. Lind, E. F. et al. Dendritic cells require the NF-κB2 pathway for cross-presentation of soluble antigens. J. Immunol. 181, 354–363 (2008).

    CAS  PubMed  Google Scholar 

  102. Katakam, A. K. et al. Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells. Proc. Natl Acad. Sci. USA 112, 14664–14669 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hammer, G. E. & Ma, A. Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu. Rev. Immunol. 31, 743–791 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Tas, S. W. et al. Noncanonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 110, 1540–1549 (2007).

    CAS  PubMed  Google Scholar 

  105. Kim, N. S. et al. Chimeric vaccine stimulation of human dendritic cell indoleamine 2, 3-dioxygenase occurs via the non-canonical NF-κB pathway. PLoS ONE 11, e0147509 (2016).

    PubMed  PubMed Central  Google Scholar 

  106. Choudhary, S., Boldogh, S., Garofalo, R., Jamaluddin, M. & Brasier, A. R. Respiratory syncytial virus influences NF-κB-dependent gene expression through a novel pathway involving MAP3K14/NIK expression and nuclear complex formation with NF-κB2. J. Virol. 79, 8948–8959 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Willmann, K. L. et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat. Commun. 5, 5360 (2014).

    PubMed  Google Scholar 

  108. Chen, K. et al. Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am. J. Hum. Genet. 93, 812–824 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lee, C. E. et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 124, 2964–2972 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lindsley, A. W. et al. Combined immune deficiency in a patient with a novel NFKB2 mutation. J. Clin. Immunol. 34, 910–915 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. Mesin, L., Ersching, J. & Victora, G. D. Germinal center B cell dynamics. Immunity 45, 471–482 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Caamano, J. H. et al. Nuclear factor (NF)-κ B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J. Exp. Med. 187, 185–196 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Franzoso, G. et al. Mice deficient in nuclear factor (NF)-κ B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J. Exp. Med. 187, 147–159 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. Mills, D. M., Bonizzi, G., Karin, M. & Rickert, R. C. Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals. Proc. Natl Acad. Sci. USA 104, 6359–6364 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    CAS  PubMed  Google Scholar 

  117. Brightbill, H. D. et al. Conditional deletion of NF-κB-inducing kinase (NIK) in adult mice disrupts mature B cell survival and activation. J. Immunol. 195, 953–964 (2015).

    CAS  PubMed  Google Scholar 

  118. Hahn, M., Macht, A., Waisman, A. & Hovelmeyer, N. NF-κB-inducing kinase is essential for B-cell maintenance in mice. Eur. J. Immunol. 46, 732–741 (2016).

    CAS  PubMed  Google Scholar 

  119. De Silva, N. S. et al. Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development. Proc. Natl Acad. Sci. USA 113, 9063–9068 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Linterman, M. A. & Vinuesa, C. G. Signals that influence T follicular helper cell differentiation and function. Semin. Immunopathol. 32, 183–196 (2010).

    CAS  PubMed  Google Scholar 

  121. Hu, H. et al. Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development. Proc. Natl Acad. Sci. USA 108, 12827–12832 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Liu, Y. et al. Novel NFKB2 mutation in early-onset CVID. J. Clin. Immunol. 34, 686–690 (2014).

    CAS  PubMed  Google Scholar 

  123. Brue, T. et al. Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. BMC Med. Genet. 15, 139 (2014).

    PubMed  PubMed Central  Google Scholar 

  124. Shin, C. et al. CD8alpha− dendritic cells induce antigen-specific T follicular helper cells generating efficient humoral immune responses. Cell Rep. 11, 1929–1940 (2015).

    CAS  PubMed  Google Scholar 

  125. O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Li, Y. et al. Cell intrinsic role of NF-κB-inducing kinase in regulating T cell-mediated immune and autoimmune responses. Sci. Rep. 6, 22115 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Rowe, A. M. et al. A cell-intrinsic requirement for NF-κB-inducing kinase in CD4 and CD8 T cell memory. J. Immunol. 191, 3663–3672 (2013).

    CAS  PubMed  Google Scholar 

  128. Tamura, C. et al. Impaired function of dendritic cells in alymphoplasia (aly/aly) mice for expansion of CD25+CD4+ regulatory T cells. Autoimmunity 39, 445–453 (2006).

    CAS  PubMed  Google Scholar 

  129. Murray, S. E. Cell-intrinsic role for NF-κ B-inducing kinase in peripheral maintenance but not thymic development of Foxp3+ regulatory T cells in mice. PLoS ONE 8, e76216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Elewaut, D. et al. NIK-dependent RelB activation defines a unique signaling pathway for the development of Vα14i NKT Cells. J. Exp. Med. 16, 1623–1633 (2003).

    Google Scholar 

  131. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Mair, F. et al. The NFκB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing gammadelta T cells. eLife 4, e10087 (2015).

    PubMed  PubMed Central  Google Scholar 

  133. Ashley, N. T., Weil, Z. M. & Nelson, R. J. Inflammation: mechanisms, costs, and natural variation. Annu. Rev. Ecol. Evol. Syst. 43, 385–406 (2012).

    Google Scholar 

  134. Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010).

    CAS  PubMed  Google Scholar 

  135. McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

    CAS  PubMed  Google Scholar 

  136. Noort, A. R., Tak, P. P. & Tas, S. W. Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde? Arthritis Res. Ther. 17, 15 (2015).

    PubMed  PubMed Central  Google Scholar 

  137. Vinay, D. S. & Kwon, B. S. Targeting TNF superfamily members for therapeutic intervention in rheumatoid arthritis. Cytokine 57, 305–312 (2012).

    CAS  PubMed  Google Scholar 

  138. Noort, A. R. et al. NF-κB-inducing kinase is a key regulator of inflammation-induced and tumour-associated angiogenesis. J. Pathol. 234, 375–385 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Maijer, K. I. et al. Nuclear factor-κB-inducing kinase is expressed in synovial endothelial cells in patients with early arthritis and correlates with markers of inflammation: a prospective cohort study. J. Rheumatol 42, 1573–1581 (2015).

    CAS  PubMed  Google Scholar 

  140. Noort, A. R. et al. Tertiary lymphoid structures in rheumatoid arthritis: NF-κB-inducing kinase-positive endothelial cells as central players. Am. J. Pathol. 185, 1935–1943 (2015).

    CAS  PubMed  Google Scholar 

  141. Baum, R. & Gravallese, E. M. Bone as a target organ in rheumatic disease: impact on osteoclasts and osteoblasts. Clin. Rev. Allergy Immunol. 51, 1–15 (2016).

    PubMed  PubMed Central  Google Scholar 

  142. Aya, K. et al. NF-κB-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis. J. Clin. Invest. 115, 1848–1854 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Yao, Z., Xing, L. & Boyce, B. F. NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism. J. Clin. Invest. 119, 3024–3034 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Xiu, Y. et al. Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation. J. Clin. Invest. 124, 297–310 (2014).

    CAS  PubMed  Google Scholar 

  145. Yang, C. et al. NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis. PLoS ONE 5, e15383 (2010).

    PubMed  PubMed Central  Google Scholar 

  146. Wei, F., Chang, Y. & Wei, W. The role of BAFF in the progression of rheumatoid arthritis. Cytokine 76, 537–544 (2015).

    CAS  PubMed  Google Scholar 

  147. Mackay, F. & Tangye, S. G. The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers. Curr. Opin. Pharmacol. 4, 347–354 (2004).

    CAS  PubMed  Google Scholar 

  148. Kaul, A. et al. Systemic lupus erythematosus. Nat. Rev. Dis. Primers 2, 16039 (2016).

    PubMed  Google Scholar 

  149. Sanz, I. & Lee, F. E. B cells as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 326–337 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhang, J. et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J. Immunol. 166, 6–10 (2001).

    CAS  PubMed  Google Scholar 

  151. Petri, M. et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 58, 2453–2459 (2008).

    CAS  PubMed  Google Scholar 

  152. Stohl, W. Inhibition of B cell activating factor (BAFF) in the management of systemic lupus erythematosus (SLE). Expert Rev. Clin. Immunol. http://dx.doi.org/10.1080/1744666X.2017.1291343 (2017).

  153. Zhang, H. & Sun, S. C. NF-κB in inflammation and renal diseases. Cell Biosci. 5, 63 (2015).

    PubMed  PubMed Central  Google Scholar 

  154. McCarthy, D. D. et al. Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. J. Clin. Invest. 121, 3991–4002 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Poveda, J. et al. TWEAK/Fn14 and non-canonical NF-κB signaling in kidney disease. Front. Immunol. 4, 447 (2013).

    PubMed  PubMed Central  Google Scholar 

  156. Sakai, N. et al. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc. Natl Acad. Sci. USA 103, 14098–14103 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Sanz, A. B. et al. TWEAK activates the non-canonical NFκB pathway in murine renal tubular cells: modulation of CCL21. PLoS ONE 5, e8955 (2010).

    PubMed  PubMed Central  Google Scholar 

  158. Valino-Rivas, L. et al. Non-canonical NFκB activation promotes chemokine expression in podocytes. Sci. Rep. 6, 28857 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).

    CAS  PubMed  Google Scholar 

  160. Choudhary, S. et al. NF-κB-inducing kinase (NIK) mediates skeletal muscle insulin resistance: blockade by adiponectin. Endocrinology 152, 3622–3627 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Sheng, L. et al. NF-κB-inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nat. Med. 18, 943–949 (2012). This is a key report demonstrating the involvement of NIK in metabolic diseases.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Starkey, J. M. et al. Diabetes-induced activation of canonical and noncanonical nuclear factor-κB pathways in renal cortex. Diabetes 55, 1252–1259 (2006).

    CAS  PubMed  Google Scholar 

  163. Malle, E. K. et al. Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity. J. Exp. Med. 212, 1239–1254 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Kiechl, S. et al. Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat. Med. 19, 358–363 (2013).

    CAS  PubMed  Google Scholar 

  165. Kim, W. H. et al. Additive activation of hepatic NF-κB by ethanol and hepatitis B protein X (HBX) or HCV core protein: involvement of TNF-alpha receptor 1-independent and -dependent mechanisms. FASEB J. 15, 2551–2553 (2001).

    CAS  PubMed  Google Scholar 

  166. Shen, H. et al. Mouse hepatocyte overexpression of NF-κB-inducing kinase (NIK) triggers fatal macrophage-dependent liver injury and fibrosis. Hepatology 60, 2065–2076 (2014).

    CAS  PubMed  Google Scholar 

  167. Ren, X. et al. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. FASEB J. 31, 711–718 (2017).

    CAS  PubMed  Google Scholar 

  168. Simmons, S. B., Pierson, E. R., Lee, S. Y. & Goverman, J. M. Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 34, 410–422 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Hofmann, J., Mair, F., Greter, M., Schmidt-Supprian, M. & Becher, B. NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses. J. Exp. Med. 208, 1917–1929 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Hussman, J. P. et al. GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis. Genes Immun. 17, 305–312 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Etemadi, N. et al. TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of sphingosine kinase 1. eLife 4, e10592 (2015).

    PubMed  PubMed Central  Google Scholar 

  172. Cai, Y. et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35, 596–610 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Eshima, K. et al. Significant involvement of nuclear factor-κB-inducing kinase in proper differentiation of alphabeta and gammadelta T cells. Immunology 141, 222–232 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Burkitt, M. D. et al. NF-κB1, NF-κB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice. J. Pathol. 236, 326–336 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Banoth, B. et al. Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection. eLife 4, e05648 (2015).

    PubMed Central  Google Scholar 

  176. Wang, Y. et al. Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32, 403–413 (2010).

    PubMed  PubMed Central  Google Scholar 

  177. Giacomin, P. R. et al. Epithelial-intrinsic IKKalpha expression regulates group 3 innate lymphoid cell responses and antibacterial immunity. J. Exp. Med. 212, 1513–1528 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the author's laboratory is supported by grants from the US National Institutes of Health (AI057555, AI064639, GM84459 and AI104519) and the Cancer Prevention Research Institute of Texas (RP140244 and RP150235).

Author information

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, MD Anderson Cancer Center UT Heath Graduate School of Biomedical Sciences, 7455 Fannin Street, Box 902, Houston, 77030, Texas, USA

    Shao-Cong Sun

Authors
  1. Shao-Cong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shao-Cong Sun.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Glossary

Tumour necrosis factor receptor (TNFR) superfamily

A large family of cytokine receptors that are engaged by members of the TNF superfamily of cytokines and mediate signal transduction.

Epidermal growth factor receptor

(EGFR). A receptor tyrosine kinase that responds to the growth factor EGF and mediates cell growth and survival by triggering several intracellular signalling pathways.

p63

A p53 homologue produced as two main isoforms, TAp63 and ΔNp63, with ΔNp63 lacking the N-terminal typical transactivation domain and functioning as a dominant-negative form to promote oncogenesis.

Tripartite motif-containing protein 29

(TRIM29). A member of the TRIM family implicated in oncogenesis.

Stromal organizer cells

Matrix cells of mesenchymal origin that characteristically express the cell adhesion molecules VCAM1 and ICAM1 and the TNFR member LTβR and are required for lymphoid organ development.

Cross-priming

A mechanism of CD8+ T cell priming, in which antigen-presenting cells take up extracellular antigens, process and present them with MHC class I molecules to CD8+ T cells.

Small interfering RNA

(siRNA). Short double-stranded RNA molecules, typically 20–25 bp in length, which bind to and induce degradation of mRNAs with complementary sequences, thereby interfering with production of the corresponding proteins.

Common variable immunodeficiency

A frequently diagnosed and heterogeneous type of primary immunodeficiency characterized by low to undetectable levels of antibodies and increased susceptibility to infections.

Experimental autoimmune encephalomyelitis

(EAE). A commonly used animal model of the autoimmune neuroinflammatory disease multiple sclerosis, characterized by infiltration of the central nervous system with T cells and monocytes that cause inflammation and demyelination leading to limb paralysis.

Rheumatoid arthritis

(RA). An autoimmune disease characterized by chronic inflammation in the joints and destruction of cartilage and bone.

Systemic lupus erythematosus

(SLE). An autoimmune disease characterized by chronic inflammation throughout the body, causing tissue damage in multiple organs.

SMAC mimetics

A class of small-molecule compounds that bind to and antagonize cIAP by mimicking the endogenous IAP antagonist SMAC.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 17, 545–558 (2017). https://doi.org/10.1038/nri.2017.52

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2017.52

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