Nuclear Factor-κB in Immunity and Inflammation: The Treg and Th17 Connection

  • Qingguo Ruan
  • Youhai H. ChenEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 946)


Although nuclear factor-κB (NF-κB) is generally considered to be a pro-inflammatory transcription factor, recent studies indicate that it also plays a critical role in the development of an anti-inflammatory T cell subset called regulatory T (Treg ) cells. Two NF-κB proteins, c-Rel and p65, drive the development of Treg cells by promoting the formation of a Foxp3-specific enhanceosome. Consequently, c-Rel -deficient mice have marked reductions in Treg cells, and c-Rel -deficient T cells are compromised in Treg cell differentiation. However, with the exception of Foxp3, most NF-κB target genes in immune cells are pro-inflammatory. These include several Th17 -related cytokine genes and the retinoid-related orphan receptor-γ (Rorg or Rorc) that specifies Th17 differentiation and lineage-specific function. T cells deficient in c-Rel or p65 are significantly compromised in Th17 differentiation, and c-Rel -deficient mice are defective in Th17 responses. Thus, NF-κB is required for the development of both anti-inflammatory Treg and pro-inflammatory Th17 cells.


NF-κB c-Rel Inflammation Th17 Treg 


  1. Bakalkin, G., Yakovleva, T., and Terenius, L. (1993) NF-kappa B-like factors in the murine brain. Developmentally-regulated and tissue-specific expression. Brain Research Molecular Brain Research 20, 137-146.PubMedCrossRefGoogle Scholar
  2. Barnes, P. J., and Karin, M. (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. New England Journal of Medicine 336, 1066-1071.PubMedCrossRefGoogle Scholar
  3. Beg, A. A., and Baltimore, D. (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274, 782-784.PubMedCrossRefGoogle Scholar
  4. Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., and Baltimore, D. (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376, 167-170.PubMedCrossRefGoogle Scholar
  5. Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., and Ochs, H. D. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27, 20-21.PubMedCrossRefGoogle Scholar
  6. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., and Kuchroo, V. K. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235-238.PubMedCrossRefGoogle Scholar
  7. Bommireddy, R., and Doetschman, T. (2007) TGFbeta1 and Treg cells: alliance for tolerance. Trends in Molecular Medicine 13, 492-501.PubMedCrossRefGoogle Scholar
  8. Brownell, E., Mathieson, B., Young, H. A., Keller, J., Ihle, J. N., and Rice, N. R. (1987) Detection of c-rel-related transcripts in mouse hematopoietic tissues, fractionated lymphocyte populations, and cell lines. Molecular & Cellular Biology 7, 1304-1309.Google Scholar
  9. Bull, P., Morley, K. L., Hoekstra, M. F., Hunter, T., and Verma, I. M. (1990) The mouse c-rel protein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain. Molecular & Cellular Biology 10, 5473-5485.Google Scholar
  10. Bunting, K., Rao, S., Hardy, K., Woltring, D., Denyer, G. S., Wang, J., Gerondakis, S., and Shannon, M. F. (2007) Genome-wide analysis of gene expression in T cells to identify targets of the NF-kappa B transcription factor c-Rel. Journal of Immunology 178, 7097-7109.Google Scholar
  11. Caamano, J. H., Rizzo, C. A., Durham, S. K., Barton, D. S., Raventos-Suarez, C., Snapper, C. M., and Bravo, R. (1998) Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. Journal of Experimental Medicine 187, 185-196.Google Scholar
  12. Carmody, R. J., Ruan, Q., Liou, H.-C., and Chen, Y. H. (2007a) Essential roles of c-Rel in Toll-like receptor-induced interleukin-23 p19 gene expression in dendritic cells. Journal of Immunology 178, 186-191.Google Scholar
  13. Carmody, R. J., Ruan, Q., Liou, H. C., and Chen, Y. H. (2007b) Essential roles of c-Rel in TLR-induced IL-23 p19 gene expression in dendritic cells. Journal of Immunology 178, 186-191.Google Scholar
  14. Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G., and Wahl, S. M. (2003) Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. Journal of Experimental Medicine 198, 1875-1886.PubMedCrossRefGoogle Scholar
  15. Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A., and Weiner, H. L. (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237-1240.PubMedCrossRefGoogle Scholar
  16. Cho, M. L., Kang, J. W., Moon, Y. M., Nam, H. J., Jhun, J. Y., Heo, S. B., Jin, H. T., Min, S. Y., Ju, J. H., Park, K. S., et al. (2006) STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. Journal of Immunology 176, 5652-5661.Google Scholar
  17. Chung, Y., Chang, S. H., Martinez, G. J., Yang, X. O., Nurieva, R., Kang, H. S., Ma, L., Watowich, S. S., Jetten, A. M., Tian, Q., et al. (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576-587.Google Scholar
  18. Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., et al. (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744-748.Google Scholar
  19. Deenick, E. K., Elford, A. R., Pellegrini, M., Hall, H., Mak, T. W., and Ohashi, P. S. (2010) c-Rel but not NF-kappaB1 is important for T regulatory cell development. European Journal of Immunology 40, 677-681.Google Scholar
  20. Doi, T. S., Takahashi, T., Taguchi, O., Azuma, T., and Obata, Y. (1997) NF-kappa B 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 185, 953-961.Google Scholar
  21. Donovan, C. E., Mark, D. A., He, H. Z., Liou, H. C., Kobzik, L., Wang, Y., De Sanctis, G. T., Perkins, D. L., and Finn, P. W. (1999) NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation. Journal of Immunology 163, 6827-6833.Google Scholar
  22. Durant, L., Watford, W. T., Ramos, H. L., Laurence, A., Vahedi, G., Wei, L., Takahashi, H., Sun, H., Kanno, Y., F., P., et al. (2010) Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis. Immunity 32, 605-615.Google Scholar
  23. Fontenot, J. D., and Rudensky, A. Y. (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nature Immunology 6, 331-337.Google Scholar
  24. Franzoso, G., Carlson, L., Poljak, L., Shores, E. W., Epstein, S., Leonardi, A., Grinberg, A., Tran, T., Scharton-Kersten, T., Anver, M., et al. (1998) Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. Journal of Experimental Medicine 187, 147-159.Google Scholar
  25. Gerondakis, S., Grossmann, M., Nakamura, Y., Pohl, T., and Grumont, R. (1999) Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function: transgenics and knockouts. Oncogene 18, 6888-6895.PubMedCrossRefGoogle Scholar
  26. Gerondakis, S., Grumont, R., Gugasyan, R., Wong, L., Isomura, I., Ho, W., and Banerjee, A. (2006) Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25, 6781-6799.PubMedCrossRefGoogle Scholar
  27. Gerondakis, S., Grumont, R., Rourke, I., and Grossmann, M. (1998) The regulation and roles of Rel/NF-kappa B transcription factors during lymphocyte activation. Curr Opin Immunol 10, 353-359.PubMedCrossRefGoogle Scholar
  28. Gerondakis, S., Strasser, A., Metcalf, D., Grigoriadis, G., Scheerlinck, J. Y., and Grumont, R. J. (1996) 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 93, 3405-3409.PubMedCrossRefGoogle Scholar
  29. Godfrey, V. L., Wilkinson, J. E., Rinchik, E. M., and Russell, L. B. (1991) Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education. Proc Natl Acad Sci U S A 88, 5528-5532.PubMedCrossRefGoogle Scholar
  30. Gonzalez, A., Katz, J. D., Mattei, M. G., Kikutani, H., Benoist, C., and Mathis, D. (1997) Genetic control of diabetes progression. Immunity 7, 873-883.PubMedCrossRefGoogle Scholar
  31. Grumont, R. J., and Gerondakis, S. (1990a) The murine c-rel proto-oncogene encodes two mRNAs the expression of which is modulated by lymphoid stimuli. Oncogene Research 5, 245-254.Google Scholar
  32. Grumont, R. J., and Gerondakis, S. (1990b) Murine c-rel transcription is rapidly induced in T-cells and fibroblasts by mitogenic agents and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Cell Growth & Differentiation 1, 345-350.Google Scholar
  33. Hilliard, B., Mason, N., Xu, L., Sun, J., Lamhamedi-Cherradi, S.-E., Liou, H.-C., Hunter, C., and Chen, Y. (2002) Critical Roles of c-Rel in Autoimmune Inflammation and Helper T Cell Differentiation. Journal of Clinical Investigation 110, 843-850.PubMedGoogle Scholar
  34. Huguet, C., Bouali, F., Enrietto, P. J., Stehelin, D., Vandenbunder, B., and Abbadie, C. (1998) The avian transcription factor c-Rel is expressed in lymphocyte precursor cells and antigen-presenting cells during thymus development. Developmental Immunology 5, 247-261.PubMedCrossRefGoogle Scholar
  35. Isomura, I., Palmer, S., Grumont, R. J., Bunting, K., Hoyne, G., Wilkinson, N., Banerjee, A., Proietto, A., Gugasyan, R., Li, W., et al. (2009) c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med 206, 3001-3014.Google Scholar
  36. Ivanov, II, McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., and Littman, D. R. (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121-1133.Google Scholar
  37. Kaltschmidt, C., Kaltschmidt, B., Lannes-Vieira, J., Kreutzberg, G. W., Wekerle, H., Baeuerle, P. A., and Gehrmann, J. (1994a) Transcription factor NF-kappa B is activated in microglia during experimental autoimmune encephalomyelitis. Journal of Neuroimmunology 55, 99-106.CrossRefGoogle Scholar
  38. Kaltschmidt, C., Kaltschmidt, B., Neumann, H., Wekerle, H., and Baeuerle, P. A. (1994b) Constitutive NF-kappa B activity in neurons. Molecular & Cellular Biology 14, 3981-3992.Google Scholar
  39. Kaltschmidt, B., Uherek, M., Volk, B., Baeuerle, P. A., and Kaltschmidt, C. (1997) Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 94, 2642-2647.Google Scholar
  40. Kim, C. H. (2006) Migration and function of FoxP3+ regulatory T cells in the hematolymphoid system. Experimental Hematology 34, 1033-1040.PubMedCrossRefGoogle Scholar
  41. Kim, J. M., and Rudensky, A. (2006) The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunological Reviews 212, 86-98.PubMedCrossRefGoogle Scholar
  42. Kretschmer, K., Apostolou, I., Jaeckel, E., Khazaie, K., and von Boehmer, H. (2006) Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer. Immunological Reviews 212, 163-169.PubMedCrossRefGoogle Scholar
  43. Kutlu, B., Darville, M. I., Cardozo, A. K., and Eizirik, D. L. (2003) Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic beta-cells. Diabetes 52, 348-355.PubMedCrossRefGoogle Scholar
  44. Kwon, G., Corbett, J. A., Rodi, C. P., Sullivan, P., and McDaniel, M. L. (1995) Interleukin-1 beta-induced nitric oxide synthase expression by rat pancreatic beta-cells: evidence for the involvement of nuclear factor kappa B in the signaling mechanism. Endocrinology 136, 4790-4795.PubMedCrossRefGoogle Scholar
  45. Lal, G., Zhang, N., Van Der Touw, W., Ding, Y., Ju, W., Bottinger, E., Reid, P., Levy, D., and Bromberg, J. (2009) Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation. Journal of Immunology 182, 259-273.Google Scholar
  46. Lamhamedi-Cherradi, S. E., Zheng, S., Hilliard, B. A., Xu, L., Sun, J., Alsheadat, S., Liou, H. C., and Chen, Y. H. (2003) Transcriptional regulation of type I diabetes by NF-kappa B. Journal of Immunology 171, 4886-4892.Google Scholar
  47. Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T., Kastelein, R. A., and Cua, D. J. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. Journal of Experimental Medicine 201, 233-240.PubMedCrossRefGoogle Scholar
  48. Li, M. O., Sanjabi, S., and Flavell, R. A. (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455-471.PubMedCrossRefGoogle Scholar
  49. Liang, S., Alard, P., Zhao, Y., Parnell, S., Clark, S. L., and Kosiewicz, M. M. (2005) Conversion of CD4+ CD25 cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. Journal of Experimental Medicine 201, 127-137.PubMedCrossRefGoogle Scholar
  50. Liou, H. C., Jin, Z., Tumang, J., Andjelic, S., Smith, K. A., and Liou, M. L. (1999) c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. International Immunology 11, 361-371.PubMedCrossRefGoogle Scholar
  51. Liu, Y., Zhang, P., Li, J., Kulkarni, A. B., Perruche, S., and Chen, W. (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nature Immunology 9, 632-640.PubMedCrossRefGoogle Scholar
  52. Lohr, J., Knoechel, B., and Abbas, A. K. (2006) Regulatory T cells in the periphery. Immunological Reviews 212, 149-162.PubMedCrossRefGoogle Scholar
  53. Long, M., Park, S. G., Strickland, I., Hayden, M. S., and Ghosh, S. (2009) Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921-931.PubMedCrossRefGoogle Scholar
  54. Lu, T., Tian, L., Han, Y., Vogelbaum, M., and Stark, G. R. (2007) Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways. Proceedings of the National Academy of Sciences of the United States of America 104, 4365-4370.Google Scholar
  55. Marie, J. C., Letterio, J. J., Gavin, M., and Rudensky, A. Y. (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. Journal of Experimental Medicine 201, 1061-1067.PubMedCrossRefGoogle Scholar
  56. Natoli, G., Saccani, S., Bosisio, D., and Marazzi, I. (2005) Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time. Nature Immunology 6, 439-445.Google Scholar
  57. O’Garra, A., and Vieira, P. (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10, 801-805.Google Scholar
  58. Pahl, H. L. (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18, 6853-6866.PubMedCrossRefGoogle Scholar
  59. Robbins, M. A., Maksumova, L., Pocock, E., and Chantler, J. K. (2003) Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL). Endocrinology 144, 4616-4625.PubMedCrossRefGoogle Scholar
  60. Romagnani, S. (1997) The Th1/Th2 paradigm. Immunology Today 18, 263-266.PubMedCrossRefGoogle Scholar
  61. Ruan, Q., Kameswaran, V., Tone, Y., Li, L., Liou, H. C., Greene, M. I., Tone, M., and Chen, Y. H. (2009) Development of Foxp3(+) regulatory T cells is driven by the c-Rel enhanceosome. Immunity 31, 932-940.PubMedCrossRefGoogle Scholar
  62. Sakaguchi, S. (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunology 6, 345-352.PubMedCrossRefGoogle Scholar
  63. Sakaguchi, S., Ono, M., Setoguchi, R., Yagi, H., Hori, S., Fehervari, Z., Shimizu, J., Takahashi, T., and Nomura, T. (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunological Reviews 212, 8-27.PubMedCrossRefGoogle Scholar
  64. Sha, W. C., Liou, H. C., Tuomanen, E. I., and Baltimore, D. (1995) Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80, 321-330.PubMedCrossRefGoogle Scholar
  65. Shevach, E. M. (2006) From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195-201.Google Scholar
  66. Shevach, E. M., DiPaolo, R. A., Andersson, J., Zhao, D. M., Stephens, G. L., and Thornton, A. M. (2006) The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunological Reviews 212, 60-73.PubMedCrossRefGoogle Scholar
  67. Shim, J. H., Xiao, C., Paschal, A. E., Bailey, S. T., Rao, P., Hayden, M. S., Lee, K. Y., Bussey, C., Steckel, M., Tanaka, N., et al. (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes & Development 19, 2668-2681.Google Scholar
  68. Simek, S., and Rice, N. R. (1988) Detection and characterization of the protein encoded by the chicken c-rel protooncogene. Oncogene Research 2, 103-119.Google Scholar
  69. Strasser, A., Grumont, R. J., Stanley, M. L., and Gerondakis, S. (1999) The transcriptional regulator Rel is essential for antigen receptor-mediated stimulation of mature T cells but dispensable for positive and negative selection of thymocytes and T cell apoptosis. European Journal of Immunology 29, 928-935.PubMedCrossRefGoogle Scholar
  70. Sutton, C., Brereton, C., Keogh, B., Mills, K. H., and Lavelle, E. C. (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. Journal of Experimental Medicine 203, 1685-1691.PubMedCrossRefGoogle Scholar
  71. Tang, Q., Henriksen, K. J., Boden, E. K., Tooley, A. J., Ye, J., Subudhi, S. K., Zheng, X. X., Strom, T. B., and Bluestone, J. A. (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. Journal of Immunology 171, 3348-3352.Google Scholar
  72. Thomas, L. H., Friedland, J. S., Sharland, M., and Becker, S. (1998) Respiratory syncytial virus-induced RANTES production from human bronchial epithelial cells is dependent on nuclear factor-kappa B nuclear binding and is inhibited by adenovirus-mediated expression of inhibitor of kappa B alpha. Journal of Immunology 161, 1007-1016.Google Scholar
  73. Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M. L., Greene, M. I., and Tone, M. (2008) Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nature Immunology 9, 194-202.PubMedCrossRefGoogle Scholar
  74. Tumang, J. R., Owyang, A., Andjelic, S., Jin, Z., Hardy, R. R., Liou, M. L., and Liou, H. C. (1998) c-Rel is essential for B lymphocyte survival and cell cycle progression. European Journal of Immunology 28, 4299-4312.PubMedCrossRefGoogle Scholar
  75. Veldhoen, M., and Stockinger, B. (2006) TGFbeta1, a “Jack of all trades”: the link with pro-inflammatory IL-17-producing T cells. Trends in Immunology 27, 358-361.PubMedCrossRefGoogle Scholar
  76. Visekruna, A., Huber, M., Hellhund, A., Bothur, E., Reinhard, K., Bollig, N., Schmidt, N., Joeris, T., Lohoff, M., and Steinhoff, U. (2010) c-Rel is crucial for the induction of Foxp3(+) regulatory CD4(+) T cells but not T(H)17 cells. Eur J Immunol 40, 671-676.PubMedCrossRefGoogle Scholar
  77. Vollgraf, U., Wegner, M., and Richter-Landsberg, C. (1999) Activation of AP-1 and nuclear factor-kappaB transcription factors is involved in hydrogen peroxide-induced apoptotic cell death of oligodendrocytes. Journal of Neurochemistry 73, 2501-2509.PubMedCrossRefGoogle Scholar
  78. Wang, W., Tam, W. F., Hughes, C. C., Rath, S., and Sen, R. (1997) c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. Immunity 6, 165-174.PubMedCrossRefGoogle Scholar
  79. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M., and Murphy, K. M. (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677-688.PubMedCrossRefGoogle Scholar
  80. Weih, F., Carrasco, D., Durham, S. K., Barton, D. S., Rizzo, C. A., Ryseck, R. P., Lira, S. A., and Bravo, R. (1995) Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331-340.PubMedCrossRefGoogle Scholar
  81. Yang, X. O., Panopoulos, A. D., Nurieva, R., Chang, S. H., Wang, D., Watowich, S. S., and Dong, C. (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. Journal of Biological Chemistry 282, 9358-9363.PubMedCrossRefGoogle Scholar
  82. Yang, X. O., Pappu, B. P., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Shah, B., Panopoulos, A. D., Schluns, K. S., et al. (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28, 29-39.Google Scholar
  83. Yang, H., Thomas, D., Boffa, D. J., Ding, R., Li, B., Muthukumar, T., Sharma, V. K., Lagman, M., Luo, G. X., Kapur, S., et al. (2002) Enforced c-REL deficiency prolongs survival of islet allografts. Transplantation 74, 291-298.Google Scholar
  84. Yu, P., Haymaker, C. L., Divekar, R. D., Ellis, J. S., Hardaway, J., Jain, R., Tartar, D. M., Hoeman, C. M., Cascio, J. A., Ostermeier, A., et al. (2008) Fetal exposure to high-avidity TCR ligand enhances expansion of peripheral T regulatory cells. Journal of Immunology 181, 73-80.Google Scholar
  85. Zandi, E., Chen, Y., and Karin, M. (1998) Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. Science 281, 1360-1363.PubMedCrossRefGoogle Scholar
  86. Zandi, E., Rothwarf, D. M., Delhase, M., Hayakawa, M., and Karin, M. (1997) The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91, 243-252.PubMedCrossRefGoogle Scholar
  87. Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X. P., Forbush, K., and Rudensky, A. Y. (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808-812.PubMedCrossRefGoogle Scholar
  88. Ziegler, S. F. (2006) FOXP3: of mice and men. Annual Review of Immunology 24, 209-226.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory Medicine, 712 Stellar-Chance LaboratoriesUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations