Table of Contents Author Guidelines Submit a Manuscript
Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 239368, 9 pages
http://dx.doi.org/10.1155/2012/239368
Review Article

A Key Role for NF-κB Transcription Factor c-Rel in T-Lymphocyte-Differentiation and Effector Functions

1Institute for Medical Microbiology and Hygiene, Philipps University of Marburg, Hans Meerwein Straße 2, 35032 Marburg, Germany
2Department of Immunology, Max Planck Institute of Infection Biology, 10117 Berlin, Germany

Received 8 October 2011; Revised 13 December 2011; Accepted 31 December 2011

Academic Editor: Niels Olsen Saraiva Camara

Copyright © 2012 Alexander Visekruna et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Pasparakis, “Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases,” Nature Reviews Immunology, vol. 9, no. 11, pp. 778–788, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. S. Gerondakis, A. Strasser, D. Metcalf, G. Grigoriadis, J. P. Y. Scheerlinck, and R. J. Grumont, “Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 8, pp. 3405–3409, 1996. View at Publisher · View at Google Scholar · View at Scopus
  3. T. S. Doi, T. Takahashi, O. Taguchi, T. Azuma, and Y. Obata, “NF-κB RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses,” Journal of Experimental Medicine, vol. 185, no. 5, pp. 953–961, 1997. View at Publisher · View at Google Scholar · View at Scopus
  4. H. C. Liou, Z. Jin, J. Tumang, S. Andjelic, K. A. Smith, and M. L. Liou, “c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function,” International Immunology, vol. 11, no. 3, pp. 361–371, 1999. View at Google Scholar · View at Scopus
  5. S. Gerondakis and U. Siebenlist, “Roles of the NF-kappaB pathway in lymphocyte development and function,” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 5, Article ID a000182, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. G. Bonizzi and M. Karin, “The two NF-κB activation pathways and their role in innate and adaptive immunity,” Trends in Immunology, vol. 25, no. 6, pp. 280–288, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Schmidt-Supprian, G. Courtois, J. Tian et al., “Mature T cells depend on signaling through the IKK complex,” Immunity, vol. 19, no. 3, pp. 377–389, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. S. Sanjabi, K. J. Williams, S. Saccani et al., “A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation,” Genes and Development, vol. 19, no. 18, pp. 2138–2151, 2005. View at Publisher · View at Google Scholar · View at Scopus
  9. K. Bunting, S. Rao, K. Hardy et al., “Genome-wide analysis of gene expression in T cells to identify targets of the NF-κB transcription factor c-Rel,” Journal of Immunology, vol. 178, no. 11, pp. 7097–7109, 2007. View at Google Scholar · View at Scopus
  10. L. Wei, M. Fan, L. Xu et al., “Bioinformatic analysis reveals crel as a regulator of a subset of interferon-stimulated genes,” Journal of Interferon and Cytokine Research, vol. 28, no. 9, pp. 541–551, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. Y. C. Lu, I. Kim, E. Lye et al., “Differential role for c-Rel and C/EBPβ/δ in TLR-mediated induction of proinflammatory cytokines,” Journal of Immunology, vol. 182, no. 11, pp. 7212–7221, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. S. A. De, P. De Luca, C. Moiola et al., “Identification of new Rel/NFκB regulatory networks by focused genome location analysis,” Cell Cycle, vol. 8, no. 13, pp. 2093–2100, 2009. View at Google Scholar · View at Scopus
  13. S. C. Sun and S. C. Ley, “New insights into NF-κB regulation and function,” Trends in Immunology, vol. 29, no. 10, pp. 469–478, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. V. Heissmeyer, D. Krappmann, E. N. Hatada, and C. Scheidereit, “Shared pathways of IκB kinase-induced SCFβTrCP-mediated ubiquitination and degradation for the NF-κB precursor p105 and IκBα,” Molecular and Cellular Biology, vol. 21, no. 4, pp. 1024–1035, 2001. View at Publisher · View at Google Scholar · View at Scopus
  15. U. Senftleben, Y. Cao, G. Xiao et al., “Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway,” Science, vol. 293, no. 5534, pp. 1495–1499, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. S. Vallabhapurapu and M. Karin, “Regulation and function of NF-κB transcription factors in the immune system,” Annual Review of Immunology, vol. 27, pp. 693–733, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. A. Oeckinghaus, M. S. Hayden, and S. Ghosh, “Crosstalk in NF-kappaB signaling pathways,” Nature Immunology, vol. 12, pp. 695–708, 2011. View at Google Scholar
  18. S. E. Murray, F. Polesso, A. M. Rowe et al., “NF-kappaB-inducing kinase plays an essential T cell-intrinsic role in graft-versus-host disease and lethal autoimmunity in mice,” The Journal of Clinical Investigation, vol. 121, no. 12, pp. 4775–4786, 2011. View at Publisher · View at Google Scholar
  19. C. W. Wright, J. M. Rumble, and C. S. Duckett, “CD30 activates both the canonical and alternative NF-κB pathways in anaplastic large cell lymphoma cells,” Journal of Biological Chemistry, vol. 282, no. 14, pp. 10252–10262, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Beinke, M. P. Belich, and S. C. Ley, “The death domain of NF-κB1 p105 is essential for signal-induced p105 proteolysis,” Journal of Biological Chemistry, vol. 277, no. 27, pp. 24162–24168, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Beinke and S. C. Ley, “Functions of NF-κB1 and NF-κB2 in immune cell biology,” Biochemical Journal, vol. 382, no. 2, pp. 393–409, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. M. S. Hayden and S. Ghosh, “Signaling to NF-κB,” Genes and Development, vol. 18, no. 18, pp. 2195–2224, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Rao, M. S. Hayden, M. Long et al., “IκBβ acts to inhibit and activate gene expression during the inflammatory response,” Nature, vol. 466, no. 7310, pp. 1115–1119, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. S. T. Smale, “Hierarchies of NF-kappaB target-gene regulation,” Nature Immunology, vol. 12, no. 8, pp. 689–694, 2011. View at Google Scholar
  25. A. Hoffmann, A. Levchenko, M. L. Scott, and D. Baltimore, “The IκB-NF-κB signaling module: temporal control and selective gene activation,” Science, vol. 298, no. 5596, pp. 1241–1245, 2002. View at Publisher · View at Google Scholar · View at Scopus
  26. S. L. Werner, D. Barken, and A. Hoffmann, “Stimulus specificity of gene expression programs determined by temporal control of IKK activity,” Science, vol. 309, no. 5742, pp. 1857–1861, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. J. M. Clark, K. Aleksiyadis, A. Martin et al., “Inhibitor of kappa B epsilon (IkappaBepsilon) is a non-redundant regulator of c-Rel-dependent gene expression in murine T and B cells,” Plos ONE, vol. 6, no. 9, Article ID e24504, 2011. View at Publisher · View at Google Scholar
  28. W. F. Tam and R. Sen, “IκB family members function by different mechanisms,” Journal of Biological Chemistry, vol. 276, no. 11, pp. 7701–7704, 2001. View at Publisher · View at Google Scholar · View at Scopus
  29. D. Banerjee, H. C. Liou, and R. Sen, “C-Rel-dependent priming of naive T cells by inflammatory cytokines,” Immunity, vol. 23, no. 4, pp. 445–458, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Chen, R. Hrdlickova, J. Nehyba, D. L. Longo, H. R. Bose, and C. C. H. Lit, “Degradation of proto-oncoprotein c-Rel by the ubiquitin-proteasome pathway,” Journal of Biological Chemistry, vol. 273, no. 52, pp. 35201–35207, 1998. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Chang, W. Jin, J.-H. Chang et al., “The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity,” Nature Immunology, vol. 12, no. 10, pp. 1002–1009, 2011. View at Publisher · View at Google Scholar
  32. X. O. Yang, R. Nurieva, G. J. Martinez et al., “Molecular antagonism and plasticity of regulatory and inflammatory T cell programs,” Immunity, vol. 29, no. 1, pp. 44–56, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. K. M. Murphy and B. Stockinger, “Effector T cell plasticity: flexibility in the face of changing circumstances,” Nature Immunology, vol. 11, no. 8, pp. 674–680, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley, and B. Stockinger, “TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells,” Immunity, vol. 24, no. 2, pp. 179–189, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. B. Stockinger, M. Veldhoen, and B. Martin, “Th17 T cells: linking innate and adaptive immunity,” Seminars in Immunology, vol. 19, no. 6, pp. 353–361, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. X. O. Yang, B. P. Pappu, R. Nurieva et al., “T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ,” Immunity, vol. 28, no. 1, pp. 29–39, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. Y. Chung, S. H. Chang, G. J. Martinez et al., “Critical Regulation of Early Th17 Cell Differentiation by Interleukin-1 Signaling,” Immunity, vol. 30, no. 4, pp. 576–587, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. R. I. Nurieva, Y. Chung, D. Hwang et al., “Generation of T Follicular Helper Cells Is Mediated by Interleukin-21 but Independent of T Helper 1, 2, or 17 Cell Lineages,” Immunity, vol. 29, no. 1, pp. 138–149, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. R. I. Nurieva, Y. Chung, G. J. Martinez et al., “Bcl6 mediates the development of T follicular helper cells,” Science, vol. 325, no. 5943, pp. 1001–1005, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. E. M. Shevach, “Mechanisms of Foxp3+ T Regulatory Cell-Mediated Suppression,” Immunity, vol. 30, no. 5, pp. 636–645, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Sakaguchi, M. Miyara, C. M. Costantino, and D. A. Hafler, “FOXP3 + regulatory T cells in the human immune system,” Nature Reviews Immunology, vol. 10, no. 7, pp. 490–500, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. F. Kontgen, R. J. Grumont, A. Strasser et al., “Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression,” Genes and Development, vol. 9, no. 16, pp. 1965–1977, 1995. View at Google Scholar · View at Scopus
  43. S. Rao, S. Gerondakis, D. Woltring, and M. F. Shannon, “c-Rel is required for chromatin remodeling across the IL-2 gene promoter,” Journal of Immunology, vol. 170, no. 7, pp. 3724–3731, 2003. View at Google Scholar · View at Scopus
  44. H. C. Liou and C. Y. Hsia, “Distinctions between c-Rel and other NF-κB proteins in immunity and disease,” BioEssays, vol. 25, no. 8, pp. 767–780, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. H. C. Liou and K. A. Smith, “The roles of c-rel and interleukin-2 in tolerance: a molecular explanation of self-nonself discrimination,” Immunology and Cell Biology, vol. 89, pp. 27–32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. J. W. Pierce, C. A. Jamieson, J. L. Ross, and R. Sen, “Activation of IL-2 receptor α-chain gene by individual members of the rel oncogene family in association with serum response factor,” Journal of Immunology, vol. 155, no. 4, pp. 1972–1980, 1995. View at Google Scholar · View at Scopus
  47. G. Chen, K. Hardy, K. Bunting, S. Daley, L. Ma, and M. F. Shannon, “Regulation of the IL-21 gene by the NF-κB transcription factor c-Rel,” Journal of Immunology, vol. 185, no. 4, pp. 2350–2359, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. A. Vogelzang, H. M. McGuire, D. Yu, J. Sprent, C. R. Mackay, and C. King, “A fundamental role for interleukin-21 in the generation of T follicular helper cells,” Immunity, vol. 29, no. 1, pp. 127–137, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Ozaki, R. Spolski, C. G. Feng et al., “A critical role for IL-21 in regulating immunoglobulin production,” Science, vol. 298, no. 5598, pp. 1630–1634, 2002. View at Publisher · View at Google Scholar · View at Scopus
  50. M. A. Linterman, L. Beaton, D. Yu et al., “IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses,” Journal of Experimental Medicine, vol. 207, no. 2, pp. 353–363, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. D. Zotos, J. M. Coquet, Y. Zhang et al., “IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism,” Journal of Experimental Medicine, vol. 207, no. 2, pp. 365–378, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. H. P. Kim, L. L. Korn, A. M. Gamero, and W. J. Leonard, “Calcium-dependent activation of interleukin-21 gene expression in T cells,” Journal of Biological Chemistry, vol. 280, no. 26, pp. 25291–25297, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. M. Huber, A. Brüstle, K. Reinhard et al., “IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20846–20851, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. Q. Ruan, V. Kameswaran, Y. Tone et al., “Development of Foxp3+ regulatory T cells is driven by the c-Rel enhanceosome,” Immunity, vol. 31, no. 6, pp. 932–940, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Long, S. G. Park, I. Strickland, M. S. Hayden, and S. Ghosh, “Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor,” Immunity, vol. 31, no. 6, pp. 921–931, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. C. S. Hsieh, “Kickstarting Foxp3 with c-Rel,” Immunity, vol. 31, no. 6, pp. 852–853, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. K. B. Vang, J. Yang, A. J. Pagán et al., “Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development,” Journal of Immunology, vol. 184, no. 8, pp. 4074–4077, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. I. Isomura, S. Palmer, R. J. Grumont et al., “c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells,” Journal of Experimental Medicine, vol. 206, no. 13, pp. 3001–3014, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. Y. Zheng, S. Josefowicz, A. Chaudhry, X. P. Peng, K. Forbush, and A. Y. Rudensky, “Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate,” Nature, vol. 463, no. 7282, pp. 808–812, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. A. Visekruna, M. Huber, A. Hellhund et al., “c-Rel is crucial for the induction of Foxp3+ regulatory CD4+ T cells but not TH17 cells,” European Journal of Immunology, vol. 40, no. 3, pp. 671–676, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Gupta, S. Manicassamy, C. Vasu, A. Kumar, W. Shang, and Z. Sun, “Differential requirement of PKC-θ in the development and function of natural regulatory T cells,” Molecular Immunology, vol. 46, no. 2, pp. 213–224, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. L. L. Molinero, J. Yang, T. Gajewski, C. Abraham, M. A. Farrar, and M. L. Alegre, “CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells,” Journal of Immunology, vol. 182, no. 11, pp. 6736–6743, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. M. J. Barnes, P. Krebs, N. Harris et al., “Commitment to the regulatory t cell lineage requires CARMA1 in the thymus but not in the periphery,” Plos Biology, vol. 7, no. 3, Article ID e1000051, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. S. D. Saibil, R. G. Jones, E. K. Deenick et al., “CD4+ and CD8+ T cell survival is regulated differentially by protein kinase Ctheta c-Rel, and protein kinase B,” Journal of Immunology, vol. 178, no. 5, pp. 2932–2939, 2007. View at Google Scholar · View at Scopus
  65. L. Harling-McNabb, G. Deliyannis, D. C. Jackson, S. Gerondakis, G. Grigoriadis, and L. E. Brown, “Mice lacking the transcription factor subunit Rel can clear an influenza infection and have functional anti-viral cytotoxic T cells but do not develop an optimal antibody response,” International Immunology, vol. 11, no. 9, pp. 1431–1439, 1999. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Sanjabi, A. Hoffmann, H. C. Liou, D. Baltimore, and S. T. Smale, “Selective requirement for c-Rel during IL-12 P40 gene induction macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 23, pp. 12705–12710, 2000. View at Publisher · View at Google Scholar · View at Scopus
  67. R. Grumont, H. Hochrein, M. O'Keeffe et al., “c-Rel regulates interleukin 12 p70 expression in CD8+ dendritic cells by specifically inducing p35 gene transcription,” Journal of Experimental Medicine, vol. 194, no. 8, pp. 1021–1031, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. J. I. Kollet and T. M. Petro, “IRF-1 and NF-κB p50/cRel bind to distinct regions of the proximal murine IL-12 p35 promoter during costimulation with IFN-γ and LPS,” Molecular Immunology, vol. 43, no. 6, pp. 623–633, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Mise-Omata, E. Kuroda, J. Niikura, U. Yamashita, Y. Obata, and T. S. Doi, “A proximal κB site in the IL-23 p19 promoter is responsible for RelA- and c-Rel-dependent transcription,” Journal of Immunology, vol. 179, no. 10, pp. 6596–6603, 2007. View at Google Scholar · View at Scopus
  70. R. J. Carmody, Q. Ruan, H. C. Liou, and Y. H. Chen, “Essential roles of c-Rel in TLR-induced IL-23 p19 gene expression in dendritic cells,” Journal of Immunology, vol. 178, no. 1, pp. 186–191, 2007. View at Google Scholar · View at Scopus
  71. D. J. Boffa, B. Feng, V. Sharma et al., “Selective loss of c-Rel compromises dendritic cell activation of T lymphocytes,” Cellular Immunology, vol. 222, no. 2, pp. 105–115, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. G. Grigoriadis, Y. Zhan, R. J. Grumont et al., “The Rel subunit of NF-κB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations,” The EMBO Journal, vol. 15, no. 24, pp. 7099–7107, 1996. View at Google Scholar · View at Scopus
  73. A. Debus, J. Gläsner, M. Röllinghoff, and A. Gessner, “High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with leishmania major are interleukin-4 dependent,” Infection and Immunity, vol. 71, no. 12, pp. 7215–7218, 2003. View at Publisher · View at Google Scholar · View at Scopus
  74. K. Reinhard, M. Huber, C. Wostl et al., “c-Rel promotes type 1 and type 17 immune responses during Leishmania major infection,” European Journal of Immunology, vol. 41, no. 5, pp. 1388–1398, 2011. View at Publisher · View at Google Scholar
  75. N. J. Mason, H. C. Liou, and C. A. Hunter, “T cell-intrinsic expression of c-Rel regulates Th1 cell responses essential for resistance to toxoplasma gondii,” Journal of Immunology, vol. 172, no. 6, pp. 3704–3711, 2004. View at Google Scholar · View at Scopus
  76. N. Mason, J. Aliberti, J. C. Caamano, H. C. Liou, and C. A. Hunter, “Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli,” Journal of Immunology, vol. 168, no. 6, pp. 2590–2594, 2002. View at Google Scholar · View at Scopus
  77. B. A. Hilliard, N. Mason, L. Xu et al., “Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation,” Journal of Clinical Investigation, vol. 110, no. 6, pp. 843–850, 2002. View at Publisher · View at Google Scholar · View at Scopus
  78. G. Chen, K. Hardy, E. Pagler et al., “The NF-κB transcription factor c-Rel is required for Th17 effector cell development in experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 187, no. 9, pp. 4483–4491, 2011. View at Publisher · View at Google Scholar
  79. Y. Wang, B. H. Rickman, T. Poutahidis et al., “C-Rel is essential for the development of innate and T cell-induced colitis,” Journal of Immunology, vol. 180, no. 12, pp. 8118–8125, 2008. View at Google Scholar · View at Scopus
  80. A. Visekruna, T. Joeris, D. Seidel et al., “Proteasome-mediated degradation of IκBα and processing of p105 in Crohn disease and ulcerative colitis,” Journal of Clinical Investigation, vol. 116, no. 12, pp. 3195–3203, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. K. J. Maloy and F. Powrie, “Intestinal homeostasis and its breakdown in inflammatory bowel disease,” Nature, vol. 474, pp. 298–306, 2011. View at Publisher · View at Google Scholar
  82. R. H. Duerr, K. D. Taylor, S. R. Brant et al., “A genome-wide association study identifies IL23R as an inflammatory bowel disease gene,” Science, vol. 314, no. 5804, pp. 1461–1463, 2006. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Hue, P. Ahern, S. Buonocore et al., “Interleukin-23 drives innate and T cell-mediated intestinal inflammation,” Journal of Experimental Medicine, vol. 203, no. 11, pp. 2473–2483, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. P. P. Ahern, A. Izcue, K. J. Maloy, and F. Powrie, “The interleukin-23 axis in intestinal inflammation,” Immunological Reviews, vol. 226, no. 1, pp. 147–159, 2008. View at Publisher · View at Google Scholar · View at Scopus
  85. P. P. Ahern, C. Schiering, S. Buonocore et al., “Interleukin-23 drives intestinal inflammation through direct activity on T cells,” Immunity, vol. 33, no. 2, pp. 279–288, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. Q. Ruan, V. Kameswaran, Y. Zhang et al., “The Th17 immune response is controlled by the Rel-ROR?-ROR? T transcriptional axis,” The Journal of Experimental Medicine, vol. 208, no. 11, pp. 2321–2333, 2011. View at Publisher · View at Google Scholar
  87. N. Schmidt, E. Gonzalez, A. Visekruna et al., “Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis,” Gut, vol. 59, no. 7, pp. 896–906, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. M. Basler, M. Dajee, C. Moll, M. Groettrup, and C. J. Kirk, “Prevention of experimental colitis by a selective inhibitor of the immunoproteasome,” Journal of Immunology, vol. 185, no. 1, pp. 634–641, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Buonocore, P. P. Ahern, H. H. Uhlig et al., “Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology,” Nature, vol. 464, no. 7293, pp. 1371–1375, 2010. View at Publisher · View at Google Scholar · View at Scopus
  90. A. Geremia, C. V. Arancibia-Cárcamo, M. P. Fleming et al., “IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease,” Journal of Experimental Medicine, vol. 208, no. 6, pp. 1127–1133, 2011. View at Publisher · View at Google Scholar
  91. D. Artis, S. Shapira, N. Mason et al., “Differential requirement for NF-κB family members in control of helminth infection and intestinal inflammation,” Journal of Immunology, vol. 169, no. 8, pp. 4481–4487, 2002. View at Google Scholar · View at Scopus