24. Venkataraman L, Wang W, Sen R (1996) Differential regulation of c-Rel translocation in activated B and T cells. J Immunol 157: 1149–1155. 25. Grumont RJ, Richardson IB, Gaff C, Gerondakis S (1993) rel/NF-kappa B nuclear complexes that bind kB sites in the murine c-rel promoter are required for constitutive c-rel transcription in B-cells. Cell Growth Differ 4: 731–743. 26. Bunting K, Rao S, Hardy K, Woltring D, Denyer GS, et al. (2007) Genome- wide analysis of gene expression in T cells to identify targets of the NF-kappa B transcription factor c-Rel. J Immunol 178: 7097–7109. 27. Macian F, Lopez-Rodriguez C, Rao A (2001) Partners in transcription: NFAT and AP-1. Oncogene 20: 2476–2489. 28. McGuire KL, Iacobelli M (1997) Involvement of Rel, Fos, and Jun proteins in binding activity to the IL-2 promoter CD28 response element/AP-1 sequence in human T cells. J Immunol 159: 1319–1327. 29. Liou HC, Jin Z, Tumang J, Andjelic S, Smith KA, et al. (1999) c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. Int Immunol 11: 361–371. 30. Rao S, Gerondakis S, Woltring D, Shannon MF (2003) c-Rel is required for chromatin remodeling across the IL-2 gene promoter. J Immunol 170: 3724–3731. 31. van Kooten C, Banchereau J (2000) CD40-CD40 ligand. J Leukoc Biol 67: 2–17. 32. Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ (2004) CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22: 307–328. 33. Wang J, Wang X, Hussain S, Zheng Y, Sanjabi S, et al. (2007) Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells. J Immunol 178: 6777–6788. 34. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, et al. (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229: 152–172. 35. Castro I, Wright JA, Damdinsuren B, Hoek KL, Carlesso G, et al. (2009) B cell receptor-mediated sustained c-Rel activation facilitates late transitional B cell survival through control of B cell activating factor receptor and NF-kappaB2. J Immunol 182: 7729–7737. 36. Batten M, Groom J, Cachero TG, Qian F, Schneider P, et al. (2000) BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 192: 1453–1466. 37. Zhou HJ, Pham LV, Tamayo AT, Lin-Lee YC, Fu L, et al. (2007) Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma. Blood 110: 2121–2127. 38. Fu L, Lin-Lee YC, Pham LV, Tamayo AT, Yoshimura LC, et al. (2009) BAFF- R promotes cell proliferation and survival through interaction with IKKbeta and NF-kappaB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells. Blood 113: 4627–4636. 39. Cope AP, Londei M, Chu NR, Cohen SB, Elliott MJ, et al. (1994) Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J Clin Invest 94: 749–760. 40. Cope AP (2002) Studies of T-cell activation in chronic inflammation. Arthritis Res 4 Suppl 3: S197–211. 41. Isomaki P, Panesar M, Annenkov A, Clark JM, Foxwell BM, et al. (2001) Prolonged exposure of T cells to TNF down-regulates TCR zeta and expression of the TCR/CD3 complex at the cell surface. J Immunol 166: 5495–5507. 42. Clark JM, Annenkov AE, Panesar M, Isomaki P, Chernajovsky Y, et al. (2004) T cell receptor zeta reconstitution fails to restore responses of T cells rendered Regulation of c-Rel by IkBe in Murine Lymphocytes hyporesponsive by tumor necrosis factor alpha. Proc Natl Acad Sci U S A 101: 1696–1701. 43. Cope AP, Patel SD, Hall F, Congia M, Hubers HA, et al. (1999) T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis- associated and nonassociated HLA-DR4 alleles. Arthritis Rheum 42: 1497–1507. 44. Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, et al. (2001) The 39 untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 21: 721–730. 45. Olave IA, Reck-Peterson SL, Crabtree GR (2002) Nuclear actin and actin- related proteins in chromatin remodeling. Annu Rev Biochem 71: 755–781. 46. Visa N, Percipalle P Nuclear functions of actin. Cold Spring Harb Perspect Biol 2: a000620. 47. Memet S, Laouini D, Epinat JC, Whiteside ST, Goudeau B, et al. (1999) IkappaBepsilon-deficient mice: reduction of one T cell precursor subspecies and enhanced Ig isotype switching and cytokine synthesis. J Immunol 163: 5994–6005. 48. Shapiro VS, Truitt KE, Imboden JB, Weiss A (1997) CD28 mediates transcriptional upregulation of the interleukin-2 (IL-2) promoter through a composite element containing the CD28RE and NF-IL-2B AP-1 sites. Mol Cell Biol 17: 4051–4058. 49. Banerjee D, Liou HC, Sen R (2005) c-Rel-dependent priming of naive T cells by inflammatory cytokines. Immunity 23: 445–458. 50. Attema JL, Reeves R, Murray V, Levichkin I, Temple MD, et al. (2002) The human IL-2 gene promoter can assemble a positioned nucleosome that becomes remodeled upon T cell activation. J Immunol 169: 2466–2476. 51. Grumont R, Lock P, Mollinari M, Shannon FM, Moore A, et al. (2004) The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. Immunity 21: 19–30. 52. Tian B, Nowak DE, Jamaluddin M, Wang S, Brasier AR (2005) Identification of direct genomic targets downstream of the nuclear factor-kappaB transcription factor mediating tumor necrosis factor signaling. J Biol Chem 280: 17435–17448. 53. Doerre S, Corley RB (1999) Constitutive nuclear translocation of NF-kappa B in B cells in the absence of I kappa B degradation. J Immunol 163: 269–277. 54. Abreu JR, Grabiec AM, Krausz S, Spijker R, Burakowski T, et al. (2009) The presumed hyporesponsive behavior of rheumatoid arthritis T lymphocytes can be attributed to spontaneous ex vivo apoptosis rather than defects in T cell receptor signaling. J Immunol 183: 621–630. 55. Goudeau B, Huetz F, Samson S, Di Santo JP, Cumano A, et al. (2003) IkappaBalpha/IkappaBepsilon deficiency reveals that a critical NF-kappaB dosage is required for lymphocyte survival. Proc Natl Acad Sci U S A 100: 15800–15805. 56. Kim D, Kolch W, Cho KH (2009) Multiple roles of the NF-kappaB signaling pathway regulated by coupled negative feedback circuits. FASEB J 23: 2796–2802. 57. Gregersen PK, Amos CI, Lee AT, Lu Y, Remmers EF, et al. (2009) REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat Genet. 58. Zhernakova A, van Diemen CC, Wijmenga C (2009) Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10: 43–55. 59. Criswell LA (2010) Gene discovery in rheumatoid arthritis highlights the CD40/ NF-kappaB signaling pathway in disease pathogenesis. Immunol Rev 233: 55–61. PLoS ONE | www.plosone.org 17 September 2011 | Volume 6 | Issue 9 | e24504