activated tumor necrosis factor a gene expression. Proc Natl Acad Sci USA 97: 3925–3929. 31. Tsytsykova AV, Goldfeld AE (2002) Inducer-specific enhanceosome formation controls tumor necrosis factor alpha gene expression in T lymphocytes. Mol Cell Biol 22: 2620–2631. 32. Barthel R, Tsytsykova AV, Barczak AK, Tsai EY, Dascher CC, et al. (2003) Regulation of tumor necrosis factor alpha gene expression by mycobacteria involves the assembly of a unique enhanceosome dependent on the coactivator proteins CBP/p300. Mol Cell Biol 23: 526–533. 33. Tsai EY, Falvo JV, Tsytsykova AV, Barczak AK, Reimold AM, et al. (2000) A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo. Mol Cell Biol 20: 6084–6094. 34. Tsytsykova AV, Rajsbaum R, Falvo JV, Ligeiro F, Neely SR, et al. (2007) Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc Natl Acad Sci USA 104: 16850–16855. 35. Biglione S, Tsytsykova AV, Goldfeld AE (2011) Monocyte-specific accessibility of a matrix attachment region in the tumor necrosis factor locus. J Biol Chem 286: 44126–44133. 36. Stenger S (2005) Immunological control of tuberculosis: role of tumour necrosis factor and more. Ann Rheum Dis 64 Suppl 4: iv24–28. 37. Quesniaux VF, Jacobs M, Allie N, Grivennikov S, Nedospasov SA, et al. (2010) TNF in host resistance to tuberculosis infection. Curr Dir Autoimmun 11: 157– 179. 38. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, et al. (2001) Tuberculosis associated with infliximab, a tumor necrosis factor a-neutralizing agent. N Engl J Med 345: 1098–1104. 39. Bermudez LE, Young LS (1988) Tumor necrosis factor, alone or in combination with IL-2, but not IFN-c, is associated with macrophage killing of Mycobacterium avium complex. J Immunol 140: 3006–3013. 40. Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P (1989) The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 56: 731–740. 41. Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, et al. (1995) Tumor necrosis factor-a is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2: 561–572. 42. Marino MW, Dunn A, Grail D, Inglese M, Noguchi Y, et al. (1997) Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci USA 94: 8093–8098. 43. Hodge MR, Ranger AM, Charles de la Brousse F, Hoey T, Grusby MJ, et al. (1996) Hyperproliferation and dysregulation of IL-4 expression in NF-ATp- deficient mice. Immunity 4: 397–405. 44. Kiani A, Viola JP, Lichtman AH, Rao A (1997) Down-regulation of IL-4 gene transcription and control of Th2 cell differentiation by a mechanism involving NFAT1. Immunity 7: 849–860. 45. Kiani A, Garcia-Cozar FJ, Habermann I, Laforsch S, Aebischer T, et al. (2001) Regulation of interferon-c gene expression by nuclear factor of activated T cells. Blood 98: 1480–1488. 46. Hermann-Kleiter N, Baier G (2010) NFAT pulls the strings during CD4+ T helper cell effector functions. Blood 115: 2989–2997. 47. Goldfeld AE, McCaffrey PG, Strominger JL, Rao A (1993) Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor a gene promoter. J Exp Med 178: 1365–1379. 48. Tsytsykova AV, Goldfeld AE (2000) Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock. J Exp Med 192: 581–586. 49. Reed MB, Domenech P, Manca C, Su H, Barczak AK, et al. (2004) A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431: 84–87. 50. Barczak AK, Domenech P, Boshoff HI, Reed MB, Manca C, et al. (2005) In vivo phenotypic dominance in mouse mixed infections with Mycobacterium tuberculosis clinical isolates. J Infect Dis 192: 600–606. 51. Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, et al. (2002) In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2- inducing cytokines. J Exp Med 195: 603–616. 52. Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, et al. (2004) IL-10- secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 172: 5986–5993. 53. Medina E, North RJ (1998) Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype. Immunology 93: 270–274. 54. Manca C, Tsenova L, Bergtold A, Freeman S, Tovey M, et al. (2001) Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-a/b. Proc Natl Acad Sci USA 98: 5752–5757. 55. Salgame P (2005) Host innate and Th1 responses and the bacterial factors that control Mycobacterium tuberculosis infection. Curr Opin Immunol 17: 374–380. 56. Flynn JL (2006) Lessons from experimental Mycobacterium tuberculosis infections. Microbes Infect 8: 1179–1188. 57. North RJ (1998) Mice incapable of making IL-4 or IL-10 display normal resistance to infection with Mycobacterium tuberculosis. Clin Exp Immunol 113: 55– 58. NFATp and TB Infection 58. Hernandez-Pando R, Aguilar D, Hernandez ML, Orozco H, Rook G (2004) Pulmonary tuberculosis in BALB/c mice with non-functional IL-4 genes: changes in the inflammatory effects of TNF-a and in the regulation of fibrosis. Eur J Immunol 34: 174–183. 59. Aly S, Laskay T, Mages J, Malzan A, Lang R, et al. (2007) Interferon-c- dependent mechanisms of mycobacteria-induced pulmonary immunopathology: the role of angiostasis and CXCR3-targeted chemokines for granuloma necrosis. J Pathol 212: 295–305. 60. Tascon RE, Soares CS, Ragno S, Stavropoulos E, Hirst EM, et al. (2000) Mycobacterium tuberculosis-activated dendritic cells induce protective immunity in mice. Immunology 99: 473–480. 61. Pedroza-Gonzalez A, Garcia-Romo GS, Aguilar-Leon D, Calderon-Amador J, Hurtado-Ortiz R, et al. (2004) In situ analysis of lung antigen-presenting cells during murine pulmonary infection with virulent Mycobacterium tuberculosis. Int J Exp Pathol 85: 135–145. 62. Erb KJ, Twardzik T, Palmetshofer A, Wohlleben G, Tatsch U, et al. (2003) Mice deficient in nuclear factor of activated T-cell transcription factor c2 mount increased Th2 responses after infection with Nippostrongylus brasiliensis and decreased Th1 responses after mycobacterial infection. Infect Immun 71: 6641– 6647. 63. Viola JP, Kiani A, Bozza PT, Rao A (1998) Regulation of allergic inflammation and eosinophil recruitment in mice lacking the transcription factor NFAT1: role of interleukin-4 (IL-4) and IL-5. Blood 91: 2223–2230. 64. Goffe B, Cather JC (2003) Etanercept: An overview. J Am Acad Dermatol 49: S105–111. 65. Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109 Suppl: S67–S79. 66. Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17: 2205–2232. 67. Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5: 472–484. 68. Serfling E, Berberich-Siebelt F, Avots A (2007) NFAT in lymphocytes: a factor for all events? Sci STKE 2007: pe42. 69. Adams LB, Mason CM, Kolls JK, Scollard D, Krahenbuhl JL, et al. (1995) Exacerbation of acute and chronic murine tuberculosis by administration of a tumor necrosis factor receptor-expressing adenovirus. J Infect Dis 171: 400–405. 70. Bean AG, Roach DR, Briscoe H, France MP, Korner H, et al. (1999) Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 162: 3504–3511. 71. Smith S, Liggitt D, Jeromsky E, Tan X, Skerrett SJ, et al. (2002) Local role for tumor necrosis factor alpha in the pulmonary inflammatory response to Mycobacterium tuberculosis infection. Infect Immun 70: 2082–2089. 72. Boom WH (1996) The role of T-cell subsets in Mycobacterium tuberculosis infection. Infect Agents Dis 5: 73–81. 73. Flynn JL, Chan J (2001) Immunology of tuberculosis. Annu Rev Immunol 19: 93–129. 74. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, et al. (1993) An essential role for interferon c in resistance to Mycobacterium tuberculosis infection. J Exp Med 178: 2249–2254. 75. Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, et al. (1993) Disseminated tuberculosis in interferon c gene-disrupted mice. J Exp Med 178: 2243–2247. 76. Agarwal S, Avni O, Rao A (2000) Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 12: 643–652. 77. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, et al. (2002) TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 3: 643–651. 78. Ansel KM, Lee DU, Rao A (2003) An epigenetic view of helper T cell differentiation. Nat Immunol 4: 616–623. 79. Barthel R, Goldfeld AE (2003) T cell-specific expression of the human TNF-a gene involves a functional and highly conserved chromatin signature in intron 3. J Immunol 171: 3612–3619. 80. Ranjbar S, Rajsbaum R, Goldfeld AE (2006) Transactivator of transcription from HIV type 1 subtype E selectively inhibits TNF gene expression via interference with chromatin remodeling of the TNF locus. J Immunol 176: 4182–4190. 81. Taylor JM, Wicks K, Vandiedonck C, Knight JC (2008) Chromatin profiling across the human tumour necrosis factor gene locus reveals a complex, cell type- specific landscape with novel regulatory elements. Nucleic Acids Res 36: 4845– 4862. 82. Cockerill PN (2008) NFAT is well placed to direct both enhancer looping and domain-wide models of enhancer function. Sci Signal 1: pe15. 83. Falvo JV, Lin CH, Tsytsykova AV, Hwang PK, Thanos D, et al. (2008) A dimer- specific function of the transcription factor NFATp. Proc Natl Acad Sci USA 105: 19637–19642. 84. Preischl EE, Pendl GG, Elbe A, Serfling E, Harrer NE, et al. (1996) Induction of the TNF-a promoter in the murine dendritic cell line 18 and the murine mast cell line CPII is differently regulated. J Immunol 157: 2645–2653. 85. McCaffrey PG, Goldfeld AE, Rao A (1994) The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-a gene transcription. J Biol Chem 269: 30445– 30450. PLoS ONE | www.plosone.org 11 July 2012 | Volume 7 | Issue 7 | e41427