Immunologic Research

, Volume 27, Issue 1, pp 85–105 | Cite as

Novel mechanisms of class II major histocompatibility complex gene regulation

  • Michael Radosevich
  • Santa Jeremy Ono


Class II MHC molecules present processed peptides from exogenous antigens to CD4+helper T lymphocytes. In so doing, they are central to immunity, driving both the humoral and cell mediated arms of the immune response. Class II MHC molecules, and the genes encoding them, are expressed primarily in cells of the immune system (B cells, thymic epithelial cells, activated T cells and professional antigen presenting cells). The expression is also under developmental control. Research over the past 20 years have provided a clear understanding of the cis-elements and transcription factors that regulate the expression of Class II MHC genes Perhaps the most critical advance has been the discovery of CIITA, a non-DNA binding activator of transcription that is a master control gene for class II gene expression. Current research is focused on understanding the situations where class II MHC gene expression occurs in a CIITA-independent pathway, and the molecular basis for this expression. Finally, significant emphasis is being placed on targeting class II MHC transcription factors to either inhibit or stimulate the immune response to transplanted tissue or in cell based vaccines. This communication outlines recent advances in this field and discusses likely areas for future research.

Key Words

Class II major histocompatibility complex genes Proteins Transcription CIITA T helper lymphocytes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Benacerraf B: Role of MHC gene products in immune regulation. Science 1981;212(4500): 1229–1238.PubMedCrossRefGoogle Scholar
  2. 2.
    Trowsdale J: Genomic structure and function in the MHC. Trends Genet. 1993;9(4):117–122.PubMedCrossRefGoogle Scholar
  3. 3.
    Sultmann H, Mayer WE, Figueroa F, O'Huigin C, Klein J: Zebrafish Mhc class II alpha chain-encoding genes: polymorphism, expression, and function. Immunogenetics 1993;38:408–420.PubMedCrossRefGoogle Scholar
  4. 4.
    Sato A, Klein D, Sultmann H, Figueroa F, O'Huigin C, Klein J: Class I mhc genes of cichlid fishes: identification, expression, and polymorphism. Immunogenetics 1997;46:63–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Monaco JJ, McDevitt HO: The LMP antigens: a stable MHC-controlled multisubunit protein complex. Hum Immunol 1986;15: 416–426.PubMedCrossRefGoogle Scholar
  6. 6.
    Martinez CK, Monaco JJ: Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene. Nature 1991; 353:664–667.PubMedCrossRefGoogle Scholar
  7. 7.
    Ploegh HL, Orr HT, Strominger JL: Molecular cloning of a human histocompatibility antigen cDNA fragment. Proc Natl Acad Sci USA 1980;77:6081–6085.PubMedCrossRefGoogle Scholar
  8. 8.
    Sood AK, Pereira D, Weissman SM: Isolation and partial nucleotide sequence of a cDNA clone for human histocompatibility antigen HLA-B by use of anoligodeoxynucleotide primer. Proc Natl Acad Sci USA 1981;78:616–620.PubMedCrossRefGoogle Scholar
  9. 9.
    Steinmetz M, Frelinger JG, Fisher D, Hunkapiller T, Pereira D, Weissman SM, et al.: Three cDNA clones encoding mouse transplantation antigens: homology to immunoglobulin genes. Cell 1981;24:125–134.PubMedCrossRefGoogle Scholar
  10. 10.
    Weiss A, Littman DR: Signal transduction by lymphocyte antigen receptors. Cell 1994;76:263–274.PubMedCrossRefGoogle Scholar
  11. 11.
    Viret C, Janeway CA Jr: MHC and T cell development. Rev Immunogenet 1999;1:91–104.PubMedGoogle Scholar
  12. 12.
    Cresswell P: Assembly, transport, and function of MHC class II molecules. Annu Rev Immunol 1994; 12:259–293.PubMedCrossRefGoogle Scholar
  13. 13.
    Guardiola J, Maffei A: Control of MHC class II gene expression in autoimmune, infectious, and neoplastic diseases. Crit Rev Immunol 1993;13:247–268.PubMedGoogle Scholar
  14. 14.
    Elhasid R, Etzioni A: Major histocompatibility complex class II deficiency: a clinical review. Blood Rev 1996;10:242–248.PubMedCrossRefGoogle Scholar
  15. 15.
    Griscelli C, Lisowska-Grospierre B, Mach B: Combined immuno-deficiency with defective expression in MHC class II genes. Immunodefic Rev 1989;1:135–153.PubMedGoogle Scholar
  16. 16.
    Klein C, Lisowska-Grospierre B, LeDeist F, Fischer A, Griscelli C: Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome. J Pediatr 1993;123: 921–928.PubMedCrossRefGoogle Scholar
  17. 17.
    Reith W, Mach B: The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 2001;19:331–373.PubMedCrossRefGoogle Scholar
  18. 18.
    Mach B, Steimle V, Martinez-Soria E, Reith W: Regulation of MHC class II genes: lessons from a disease. Annu Rev Immunol 1996;14: 301–331.PubMedCrossRefGoogle Scholar
  19. 19.
    Ting JP, Baldwin AS: Regulation of MHC gene expression. Curr Opin Immunol 1993;5:8–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Benoist C, Mathis D: Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol 1990;8:681–715.PubMedGoogle Scholar
  21. 21.
    Glimcher LH, Kara CJ: Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol 1992;10:13–49.PubMedCrossRefGoogle Scholar
  22. 22.
    Boss JM: Regulation of transcription of MHC class II genes. Curr Opin Immunol 1997;9:107–113.PubMedCrossRefGoogle Scholar
  23. 23.
    Kelly AP, Monaco JJ, Cho SG, Trowsdale J: A new human HLA class II-related locus, DM. Nature 1991;353:571–573.PubMedCrossRefGoogle Scholar
  24. 24.
    Ting JP, Wright KL, Chin KC, Brickey WJ, Li G: The DMB promoter: delineation, in vivo foot-print, trans-activation, and trans-dominant suppression. J Immunol 1997;159:5457–5462.PubMedGoogle Scholar
  25. 25.
    Taxman DJ, Cressman DE, Ting JP: Identification of class II transcriptional activator-induced genes by representational difference analysis: discoordinate regulation of the DN alpha/DO beta heterodimer. J Immunol 2000;165:1410–1416.PubMedGoogle Scholar
  26. 26.
    Brown AM, Barr CL, Ting JP: Sequences homologouse to class II MHC W, X, and Y elements mediate constitutive and IFN-gamma-induced expression of human class II-associated invariant chain gene. J Immunol 1991;146:3183–3189.PubMedGoogle Scholar
  27. 27.
    Brown AM, Wright KL, Ting JP: Human major histocompatibility complex class II-associated invariant chain gene promoter. Functional analysis and in vivo protein/DNA interactions of constitutive and IFN-gamma-induced expression. J Biol Chem 1993;268: 26,328–26,333.Google Scholar
  28. 28.
    Tai AK, Zhou G, Chau K, Ono SJ: Cis-element dependence and occupancy of the human invariant chain promoter in CIITA-dependent and-independent transcription. Mol Immunol 1999;36:447–460.PubMedCrossRefGoogle Scholar
  29. 29.
    Busch R, Mellins ED: Developing and shedding inhibitions: how MHC class II molecules reach maturity. Curr Opin Immunol 1996;8:51–58.PubMedCrossRefGoogle Scholar
  30. 30.
    Alfonso C, Karlsson L: Nonclassical MHC class II molecules. Annu Rev Immunol 2000;18: 113–142.PubMedCrossRefGoogle Scholar
  31. 31.
    Martin BK, Chin KC, Olsen JC, Skinner CA, Dey A, Ozato K, et al. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 1997;6:591–600.PubMedCrossRefGoogle Scholar
  32. 32.
    Gobin SJ, Peijnenburg A, Keijsers V, van den Elsen PJ: Site alpha is crucial for two routes of IFN gamma-induced MHC class I transactivation: the ISRE-mediated route and a novel pathway involving CIITA. Immunity 1997;6:601–611.PubMedCrossRefGoogle Scholar
  33. 33.
    Gobin SJ, Peijnenburg A, van Eggermond M, van Zutphen M, van den Berg R, van den Elsen PJ: The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes. Immunity 1998;9:531–541.PubMedCrossRefGoogle Scholar
  34. 34.
    van den Elsen PJ, Peijnenburg A, van Eggermond MC, Gobin SJ: Shared regulatory elements in the promoters of MHC class 1 and class 11 genes. Immunol Today 1998;19:308–312.PubMedCrossRefGoogle Scholar
  35. 35.
    Boss JM, Strominger JL: Regulation of a transfected human class 11 major histocom patibility complex gene in human fibroblasts. Proc Natl Acad Sci USA 1986;83:9139–9143.PubMedCrossRefGoogle Scholar
  36. 36.
    Tsang SY, Nakanishi M, Peterlin BM: Mutational analysis of the DRA promoter: cis-acting sequences and trans-acting factors. Mol Cell Biol 1990;10:711–719.PubMedGoogle Scholar
  37. 37.
    Basta PV, Sherman PA, Ting JP: Detailed delineation of aninter ferongamma-responsive element important in human HLA-DRA gene expression in a glioblastoma multiform line. Proc Natl Acad Sci USA 1988;85:8618–8622.PubMedCrossRefGoogle Scholar
  38. 38.
    Reith W, Siegrist CA, Durand B, Barras E, Mach B: Function of major histocompatibility complex class 11 promoters requires cooperative binding between factors RFX and NF-Y. Proc Natl Acad Sci USA 1994;91:554–558.PubMedCrossRefGoogle Scholar
  39. 39.
    Siegrist CA, Durand B, Emery P, David E, Hearing P, Mach B, et al.: RFX1 is identical to enhancer factor C and functions as a transactivator of the hepatitis B virus enhancer. Mol Cell Biol 1993; 13:6375–6384.PubMedGoogle Scholar
  40. 40.
    Burkly LC, Lo D, Cowing C, Palmiter RD, Brinster RL, Flavell RA: Selective expression of class 11 Ealphad gene in transgenic mice. J Immunol 1989;142:2081–2088.PubMedGoogle Scholar
  41. 41.
    Dorn A, Fehling HJ, Koch W, Le Meur M, Gerlinger P, Benoist C, et al.: B-Cell control region at the 5′ end of a major histocompa-tibility complex class 11 gene: sequences and factors. Mol Cell Biol 1988;8:3975–3987.PubMedGoogle Scholar
  42. 42.
    Sherman PA, Basta PV, Ting JP: Upstream DNA sequences required for tissue-specific expression of the HLA-DR alpha gene. Proc Natl Acad Sci USA 1987;84:4254–4258.PubMedCrossRefGoogle Scholar
  43. 43.
    Tsang SY, Nakanishi M, Peterlin BM: B-Cell-specific and interferon-gamma-inducible regulation of the HLA-DR alpha gene. Proc. Natl Acad sci USA 1988;85:8598–8602.PubMedCrossRefGoogle Scholar
  44. 44.
    Stimac E, Lyons S, Pious D: Transcription of HLA class 11 genes in the absence of B-cell-specific octamer-binding factor. Mol Cell Biol 1988;8:3734–3739.PubMedGoogle Scholar
  45. 45.
    Lion HC, Boothby MR, Glimcher LH: Distinct cloned class 11 MHC DNA binding proteins recognize the X box transcription element. Science 1988;242:69–71.CrossRefGoogle Scholar
  46. 46.
    Gaur LK, Heise ER, Ting JP: Conservation of the promoter region of DRA-like genes from nonhuman primates. Immuno genetics 1992; 35:136–139.Google Scholar
  47. 47.
    Sherman PA, Basta PV, Heguy A, Wloch MK, Roeder RG, Ting JP: The octamer motif is a B-lymphocyte-specific regulatory element of the HLA-DR alpha gene promoter. Proc Natl Acad Sci USA 1989;86:6739–6743.PubMedCrossRefGoogle Scholar
  48. 48.
    Abdulkadir SA, Krishna S, Thamos D, Maniatis T, Strominger JL, Ono SJ: Functional roles of the transcription factor Oct-2A and the high mobility group protein 1/Y in HLA-DRA gene expression. J Exp Med 1995;182:487–500.PubMedCrossRefGoogle Scholar
  49. 49.
    vilen BJ, Cogswell JP, Ting JP: Stereospecific alignment of the X and Y elements isrequired for major histocom patibility complex class II DRA promoter function. Mol Cell Biol 1991;11:2406–2415.PubMedGoogle Scholar
  50. 50.
    Vilen BJ, Penta JF, Ting JP: Structural constraints within a trimeric transcriptional regulatory region. Constitutive and interferon-gamma-inducible expression of the HLA-DRA gene. J Biol. Chem 1992;267:23,728–23,734.Google Scholar
  51. 51.
    Wright KL, Vilen BJ, Itoh-Lindstrom Y, Moore TL, Li G, Criscitiello M, et al.: CCAAT box binding protein NF-Y facilitates in vivo recruitment of upstream DNA binding transcription factors. EMBO J 1994;13:4042–4053.PubMedGoogle Scholar
  52. 52.
    Sugawara M, Scholl T, Ponath PD, Strominger JL: A factor that regulates the class II major histocom-patibility complex gene DPA is a member of a subfamily of zinc finger proteins that includes a Drosophila developmental control protein. Mol Cell Biol 1994;14:8438–8450.PubMedGoogle Scholar
  53. 53.
    Siegrist CA, Mach B: Antisense oligonucleotides specific for regulatory factor RFX-1 inhibit inducible but not constitutive expression of all major histo-compatibility complex class II genes. Eur J Immunol 1993;23:2903–2908.PubMedCrossRefGoogle Scholar
  54. 54.
    Ono SJ, Liou HC, Davidon R, Strominger JL, Glimcher LH: Human X-box-binding protein 1 isrequired for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos. Proc Natl Acad Sci USA 1991;88:4309–4312.PubMedCrossRefGoogle Scholar
  55. 55.
    Song Z, Krishna S, Thanos D, Strominger JL, Ono SJ: A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocom patibility complex class 11 genes via a repeated Cys-His domain and functions as a transcriptional repressor. J Exp Med 1994;180:1763–1774.PubMedCrossRefGoogle Scholar
  56. 56.
    Ting JP, Painter A, Zeleznik-Le NJ, MacDonald G, Moore TM, Brown A, et al.: TB-1 DNA-binding protein represses interferon gamma activation of class II major histo-compatibility complex genes. J Exp Med 1994;179:1605–1611.PubMedCrossRefGoogle Scholar
  57. 57.
    Dom A, Durand B, Marfing C, Le Meur M, Benoist C, Mathis D: Conserved major histocompatibility complex class II boxes—X and Y—are transcriptional control elements and specifically bind nuclear proteirs. Proc Natl Acad Sci USA 1987;84:6249–6253.CrossRefGoogle Scholar
  58. 58.
    Hooft van Huijsduijnen RA, Bollekens J, Dorn A, Benoist C, Mathis D: Properties of a CCAAT box-binding protein. Nucleic Acids Res 1987;15:7265–7282.PubMedCrossRefGoogle Scholar
  59. 59.
    Maity SN, de Crombrugghe B: Role of the CCAAT-binding protein cBF/NF-Y in transcription. Trends Biochem Sci 1998;23: 174–178.PubMedCrossRefGoogle Scholar
  60. 60.
    Sinha S, Kim IS, Sohn KY, de Crombrugghe B, Maity SN: Three classes of mutations in the A subunit of the CCAAT-binding factor CBF delineate functional domains involved in the three-step assembly of the CBF-DNA complex. Mol Cell Biol 1996;16:328–337.PubMedGoogle Scholar
  61. 61.
    Mantovani R, Pessara U, Tronche F, Li XY, Knapp AM, Pasqual JL, Benoist C, Mathis D: Monoclonal antibodies to NF-Y define its function in MHC class II and albumin gene transcription. EMBO J. 1992;11(9):3315–3322.PubMedGoogle Scholar
  62. 62.
    Wolffe AP: Structural and functional properties of the evolution-arily ancient Y-box family of nucleic acid binding proteins. Bioessays 1994;16:245–251.PubMedCrossRefGoogle Scholar
  63. 63.
    Didier DK, Schiffenbauer J, Woulfe SL, Zacheis M, Schwartz BD: Characterization of the cDNA encoding a protein binding to the major histocompatibility complex class 11 Y box. Proc Natl Acad Sci USA 1988;85:7322–7326.PubMedCrossRefGoogle Scholar
  64. 64.
    Masternak K, Barras E, Zufferey M, Conrad B, Corthals G, Aebersold R, et al.: A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class 11 deficiency patients. Nat Genet 1998;20:273–277.PubMedCrossRefGoogle Scholar
  65. 65.
    Durand B, Kobr M, Reith W, Mach B: Functional comple mentation of major histocompatibility complex class II regulatory mutants by the purified X-box-binding protein RFX. Mol Cell Biol 1994;14:6839–6847.PubMedGoogle Scholar
  66. 66.
    Moreno CS, Rogers EM, Brown JA, Boss JM: Regulatory factor X, a bare lymphocyte syndrome transcription factor, is a multimeric phosphoprote in complex. J Immunol 1997;158:5841–5848.PubMedGoogle Scholar
  67. 67.
    Durand B, Sperisen P, Emery P, Barras E, Zufferey M, Mach B, et al.: RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class 11 deficiency. EMBO J 1997;16:1045–1055.PubMedCrossRefGoogle Scholar
  68. 68.
    Steimle V, Durand B, Barras E, Zufferey M, Hadam MR, Mach B, et al.: A novel DNA-binding regulatory factor is mutate in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev 1995;9:1021–1032.PubMedGoogle Scholar
  69. 69.
    Nagarajan UM, Louis-Plence P, DeSandro A, Nilsen R, Bushey A, Boss JM: RFX-B is the gene respon-sible for the most commoncause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity 1999;10:153–162.PubMedCrossRefGoogle Scholar
  70. 70.
    Emery P, Durand B, Mach B, Reith W: RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom. Nucleic Acids Res 1996;24:803–807.PubMedCrossRefGoogle Scholar
  71. 71.
    Brickey WJ, Wright KL, Zhu XS, Ting JP: Analysis of the defect in IFN-gamma induction of MHC class 11 genes in G1B cells: identification of a novel and functionally critical leucine-rich motif (62-LYLYLQL-68) in the regulatory factor X 5 transcription factor. J Immunol 1999;163:6622–6630.PubMedGoogle Scholar
  72. 72.
    Villard J, Lisowska-Grospierre B, van den Elsen P, Fischer A, Reith W, Mach B: Mutation of RFXAP, a regulator of MHC class 11 genes, in primary MHC class 11 deficiency. N Engl J Med 1997;337:748–753.PubMedCrossRefGoogle Scholar
  73. 73.
    Masternak K, Muhlethaler-Mottet A, Villard J, Peretti M, Reith W: Molecular genetics of the Bare lymphocyte syndrome. Rev Immunogenet 2000;2:267–282.PubMedGoogle Scholar
  74. 74.
    Fondaneche MC, Villard J, Wiszniewski W, Jouanguy E, Etzioni A, Le Deist F, et al.: Genetic and molecular definition of complementation group D in MHC class II deficiency. Hum Mol Genet 1998;7:879–885.PubMedCrossRefGoogle Scholar
  75. 75.
    Steimle V, Siegrist CA, Mottet A, Lisowska-Grospierre B, Mach B: Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 1994;265:106–109.PubMedCrossRefGoogle Scholar
  76. 76.
    Andersson G, Peterlin BM: NF-X2 that birds to the DRA X2-box is activator protein 1. Expression cloning of c-Jun. J Immunol 1990;145:3456–3462.PubMedGoogle Scholar
  77. 77.
    Louis-Plence P, Moreno CS, boss JM: Formation of a regulatory factor X/X2 box-binding protein/nuclear factor-Y multipro-tein complex on the conserved regulatory regions of HLA class II genes. J Immunol 1997;159:3899–3909.PubMedGoogle Scholar
  78. 78.
    Moreno CS, Emery P, West JE, Durand B, Reith W, Mach B, et al.: Purified X2 binding protein (X2BP) cooperatively binds the class 11 MHC X box region in the presence of purified RFX, the X box factor deficient in the bare lymphocyte syndrome. J Immunol 1995;155:4313–4321.PubMedGoogle Scholar
  79. 79.
    Westerheide SD, Louis-Plence P, Ping D, He XF, Boss JM: HLA-DNA and HLA-DMB gene expression functions through the conserved S-X-Y region. J Immunol 1997;158:4812–4821.PubMedGoogle Scholar
  80. 80.
    Cogswell JP, Austin J, Ting JP: The W element is a positive regulator of HLA-DRA transcription in various DR+ cell types. J Immunol 1991;146:1361–1367.PubMedGoogle Scholar
  81. 81.
    Jabrane-Ferrat N, Fontes JD, Boss JM, Peterlin BM: Complex architecture of major histocompatibility comlex class II promoters: reiterated motifs and conserved protein-protein interactions. Mol Cell Biol 1996;16:4683–4690.PubMedGoogle Scholar
  82. 82.
    Muller MM, Ruppert S, Schaffner W, Matthias P: A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature 1988;336:544–551.PubMedCrossRefGoogle Scholar
  83. 83.
    Wright KL, Ting JP: In vivo foot-print analysis of the HLA-DRA gene promoter, cell-specfic interaction at the octamer site and upregulation of X box binding by interferon gamma. Proc Natl Acad Sci USA 1992;89(16):7601–7605.PubMedCrossRefGoogle Scholar
  84. 84.
    Steimle V, Otten LA, Zufferey M, Mach B: Complemenation cloning of an MHC class II transactivator mutated in hereditary MHC class 11 deficiency (or bare lymphocyte syndrome). Cell 1993; 75:135–146.PubMedGoogle Scholar
  85. 85.
    Chang CH, Fontes JD, Peterlin M, Flavell RA: Class 11 transactivator (C11TA) is sufficient for the inducible expression of major histocompatibility complex class 11 genes. J Exp Med 1994;180:1367–1374.PubMedCrossRefGoogle Scholar
  86. 86.
    Lee YJ, Benveniste EN: Statl alpha expression is involved in 1FN-gamma induction of the class II transactivator and class II MHC genes. J Immunol 1996;157:1559–1568.PubMedGoogle Scholar
  87. 87.
    Muhlethaler-Mottet A, Otten LA, Steimle V, Mach B: Espression of MHC class 11 molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. EMBO J 1997;16:2851–2860.PubMedCrossRefGoogle Scholar
  88. 88.
    O'Keefe GM, Nguyen VT, Benveniste EN: Class 11 transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10. Eur J Immunol 1999;29:1275–1285.PubMedCrossRefGoogle Scholar
  89. 89.
    Dong Y, Rohn WM, Benveniste EN: IFN-gamma regulation of the type IV class II transactivator promoter in astrocytes. J Immunol 1999; 162: 4731–4739.PubMedGoogle Scholar
  90. 90.
    Otten LA, Steimle V, Bontron S, Mach B: Quantitative control of MHC class II expression by the transactivator CIITA. Eur J Immunol 1998;28:473–478.PubMedCrossRefGoogle Scholar
  91. 91.
    Silacci P, Mottet A, Steimle V, Reith W, Mach B: Developmental extinction of major histocompatibility complex class II gene expression in plasmocytes is mediated by silencing of the transactivatorgene CIITA. J Exp Med 1994;180:1329–1336.PubMedCrossRefGoogle Scholar
  92. 92.
    Sartoris S, Valle MT, Barbaro AL, Tosi G, Cestari T, D'Agostino A, et al.: HLA class II expressioninunin-ducible hepatocarc inomacells after transfection of AIR-1 gene product CIITA: acquisition of antigen processing and presentation capacity. J Immunol 1998;161:814–820.PubMedGoogle Scholar
  93. 93.
    Sartoris S, Tosi G, De Lema Barbaro A, Cestari T, Accolla RS: Active suppression of the class II transactivator-encoding AIR-1 locus is responsible for the lack of major histocompatibility complex class II gene expression observed during differentiation from B cells to plasma cells. Eur J Immunol 1996;26:2456–2460.PubMedCrossRefGoogle Scholar
  94. 94.
    Brown JA, Rogers EM, Boss JM: The MHC class 11 transactivator (CIITA) requires conserved leucine charged domairs for interactions with the conserved W box promoter element. Nucleic Acids Res 1998; 26: 4128–4136.PubMedCrossRefGoogle Scholar
  95. 95.
    Chang CH, Flavell RA: Class II transactivatorregulates the expression of multiple genes involved in antigen presentation. J Exp Med 1995;181:765–767.PubMedCrossRefGoogle Scholar
  96. 96.
    Muhlethaler-Mottel A, Di Berardino W, Otten LA, Mach B: Activation of the MHC class II transactivator CIITA by interferon-gamma requires cooperative interaction between Statl and USF-1. Immunity 1998;8:157–166.CrossRefGoogle Scholar
  97. 97.
    Piskurich JF, Linhoff MW, Wang Y, Ting JP: Two distinct gamma interferon-inducible promoters of the major histocompatibility complex class II transactivator gene are differentially regulated by STAT1, interferon regulatory factor 1, and transforming growth factor beta. Mol Cell Biol 1999;19:431–440.PubMedGoogle Scholar
  98. 98.
    Piskurich JF, Wang Y, Linhoff MW, White LC, Ting JP: Identification of distinct regions of 5′ flanking DNA that mediate constitutive, IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II transactivator gene. J Immunol 1998;160:233–240.PubMedGoogle Scholar
  99. 99.
    Lloberas J, Soler C, Celada A: Mechanism of I-Abeta gene expression. Microbes Infect 1999;1:935–941.PubMedCrossRefGoogle Scholar
  100. 100.
    Bach EA, Aguet M, Schreiber RD: The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 1997;15:563–591.PubMedCrossRefGoogle Scholar
  101. 101.
    McCartney-Francis NL, Wahl SM: Transforming growth factor beta: a matter of life and death. J Leukoc Biol 1994;55:401–409.PubMedGoogle Scholar
  102. 102.
    Gabrielian K, Osusky R, Sippy BD, Ryan SJ, Hinton DR: Effect of TGF-beta on interferon-gamma-induced HLA-DR expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 1994;35:4253–4259.PubMedGoogle Scholar
  103. 103.
    Nandan D, Reiner NE: TGF-beta attenuates the class II transactivator and reveals an accessory pathway of IFN-gamma action. J Immunol 1997;158:1095–1101.PubMedGoogle Scholar
  104. 104.
    Zhou H, Glimcher LH: Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency. Immunity 1995;2:545–553.PubMedCrossRefGoogle Scholar
  105. 105.
    Chin KC, Li GG, Ting JP: Importance of acidic, proline/serine/threonine-rich, and GTP-binding regions in the major histcompatibility complex class II transactivator: generation of transdominant-negative mutants. Proc Natl Acad Sci. USA 1997;94:2501–2506.PubMedCrossRefGoogle Scholar
  106. 106.
    Riley JL, Westerheide SD, Price JA, Brown JA, Boss JM: Activation of class II MHC genes requires both the X box region and the class II transactivator (CIITA). Immunity 1995;2:533–543.PubMedCrossRefGoogle Scholar
  107. 107.
    Chin KC, Li G, Ting JP: Activation and transdominant suppression of MHC class 11 and HLA-DMB promoters by a series of C-terminal class II transactivator deletion, mutants. J Immunol 1997;159:2789–2794.PubMedGoogle Scholar
  108. 108.
    Bontron S, Ucla C, Mach B, Steimle V: Efficient repression of endogenous major histocompatibility complex class II expression through dominant negative CIITA mutants isolated by a functional selection strategy. Mol Cell Biol 1997;17:4249–4258.PubMedGoogle Scholar
  109. 109.
    Kretsovali A, Agalioti T, Spilianakis C, Tzortzakaki E, Merika M, Papamatheakis J: Involvement of CREB binding protein in expression of major histocompatibility complex class II genes via interaction with the class II transactivator. Mol Cell Biol 1998;18:6777–6783.PubMedGoogle Scholar
  110. 110.
    Fontes JD, Kanazawa S, Jean D, Peterlin BM: Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes. Mol Cell Biol 1999;19:941–947.PubMedGoogle Scholar
  111. 111.
    Mahanta SK, Scholl T, Yang FC, Strominger JL: Transactivation by CIITA, the type II bare lymphocyte syndrome-associated factor, requires participation of multiple regions of the TATA box binding protein. Proc Natl Acad Sci USA 1997;94:6324–6329.PubMedCrossRefGoogle Scholar
  112. 112.
    Fontes JD, Jiang B, Peterlin BM: The class II trans-activator CIITA interacts with the TBP-associated factor TAFII32. Nucleic Acids Res 1997;25:2522–2528.PubMedCrossRefGoogle Scholar
  113. 113.
    Kanazawa S, Okamoto T, Peterlin BM: Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 2000;12(1):61–70.PubMedCrossRefGoogle Scholar
  114. 114.
    De Sandro AM, Nagarajan UM, Boss JM: Associations and inter-actions between bare lymphocyte syndrome factors. Mol Cell Biol 2000;20:6587–6599.CrossRefGoogle Scholar
  115. 115.
    Zhu XS, Linhoff MW, Li G, Chin KC, Maity SN, Ting JP: Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter. Mol Cell Biol 2000;20:6051–6061.PubMedCrossRefGoogle Scholar
  116. 116.
    Masternak K, Muhlethaler-Mottet A, Villard J, Zufferey M, Steimle V, Reith W: CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with anenhanceosome complex. Genes Dev 2000;14:1156–1166.PubMedGoogle Scholar
  117. 117.
    Harton JA, Cressman DE, Chin KC, Der CJ, Ting JP: GTP binding by class II transactivator: role in nuclear import. Science 1999;285:1402–1405.PubMedCrossRefGoogle Scholar
  118. 118.
    Cressman DE, Chin KC, Taxman DJ, Ting JP: Adefect in the nuclear translocation of CIITA causes a form of type II hare lymphocyte syndrome. Immunity 1999;10:163–171.PubMedCrossRefGoogle Scholar
  119. 119.
    Hake SB, Masternak K, Kammerbauer C, Janzen C, Reith W, Steimle V: CIITA leucine-rich repeats control nuclear localization, in vivo recruitment to the major histocom-patibility complex (MHC) class II enhanceosome, and MHC class II gene transactivation. Mol Cell Biol 2000;20(20):7716–7725.PubMedCrossRefGoogle Scholar
  120. 120.
    Lennon AM, Ottone C, Rigaud G, Deaven LL, Longmire J, Fellous M, et al.: Isolation of a B-cell-specific promoter for the human class II transactivator. Immunogenetics 1997;45:266–273.PubMedCrossRefGoogle Scholar
  121. 121.
    Ghosh N, Piskurich JF, Wright G, Hassani K, Ting JP, Wright KL: A novel element and a TEF-2-like element activate the major histocompatibility complex class 11 transactivator in B-lymphocytes. J Biol Chem 1999; 274:32,342–32,350.Google Scholar
  122. 122.
    Nikcevich KM, Piskurich JF, Hellendall RP, Wang Y, Ting JP: Differential selectivity of CIITA promoter activation by IFN-gamma and IRF-1 in astrocytes and macrophages CIITA promoter activation is not affected by TNF-alpha. J Neuroimmunol 1999;99:195–204.PubMedCrossRefGoogle Scholar
  123. 123.
    Suter T, Malipiero U, Otten L, Ludewig B, Muelethaler-Mottet A, Mach B, et al.: Dendritic cells and differential usage of the MHC class II transactivator promoters in the central nervous system in experimental autoimmune encephalitis. Eur J Immunol 2000;30:794–802.PubMedCrossRefGoogle Scholar
  124. 124.
    Rohn W, Tang LP, Dong Y, Benveniste EN: IL-1 beta inhibits IFN-gamma-induced class II MHC expression by suppressing transcription of the class II transactivator gene. J Immunol 1999;162:886–896.PubMedGoogle Scholar
  125. 125.
    Harada H, Taniguchi T, Tanaka N: The role of interferon regulatory factors in the interferon system and cell growth control. Biochimic 1998;80:641–650.CrossRefGoogle Scholar
  126. 126.
    Leonard WJ, O'Shea JJ: Jaks and STATs: biological implications. Annu Rev Immunol 1998;16:293–322.PubMedCrossRefGoogle Scholar
  127. 127.
    Imada K, Leonard WJ: The Jak-STAT pathway. Mol Immunol 2000;37:1–11.PubMedCrossRefGoogle Scholar
  128. 128.
    Morris AC, Riley JL, Fleming WH, Boss JM: MHC class II gene silencing in trophoblast cells is caused by inhibition of CIITA expression. Am J Reprod Immunol 1998;40:385–394.PubMedGoogle Scholar
  129. 129.
    Morris AC, Spangler WE, Boss JM: Methylation of class II trans-activator promoter IV: a novel mechanism of MHC class II gene control. J Immunol 2000;164:4143–4149.PubMedGoogle Scholar
  130. 130.
    Blanck G: HLA class II expression in human tumor lines. Microbes Infect 1999;1:913–918.PubMedCrossRefGoogle Scholar
  131. 131.
    Kadota Y, Okumura M, Miyoshi S, Kitagawa-Sakakida S, Inoue M, Shiono H, et al.: Altered T cell development in human thymoma is related to impaiment of MHC class II transactivator expression induced by interferon-gamma (IFN-gamma). Clin Exp Immunol 2000;121:59–68.PubMedCrossRefGoogle Scholar
  132. 132.
    Miller DM, Rahill BM, Boss JM, Lairmore MD, Durbin JE, Waldman JW, et al: Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J Exp Med 1998;187:675–683.PubMedCrossRefGoogle Scholar
  133. 133.
    Le Roy E, Muhlethaler-Mottet A, Davrinche C, Mach B, Davignon JL: Escape of human cytomegalovirus from HLA-DR-restricted CD4(+) T-cell response is mediated by repression of gamma interferon-induced class II transactivator expression. J Virol 1999;73:6582–6589.PubMedGoogle Scholar
  134. 134.
    Zhong G, Fan T, Liu L: Chlamydia inhibits interferon gamma-inducible major histocom patibility complex class II expression by degradation of upstream stimulatory factor I. J Exp Med 1999;189:1931–1938.PubMedCrossRefGoogle Scholar
  135. 135.
    Fontes JD, Kanazawa S, Nekrep N, Peterlin BM: The class II transactivator CIITA is a transcriptional integrator. Microbes Infect 1999;1:863–869.PubMedCrossRefGoogle Scholar
  136. 136.
    Sauter P, Matthias P: The B cell-specific coactivator OBF-1 (OCA-B, Bob-1) is inducible in T cells and its expression is dispensable for IL-2 gene induction. Immunobiology 1997;198:207–216.PubMedGoogle Scholar
  137. 137.
    Zwilling S, Dieckmann A, Pfisterer P, Angel P, Wirth T; Inducible expression and phosphorylation of coactivator BOB.1/OBF.1 in T cells. Science 1997;277:221–225.PubMedCrossRefGoogle Scholar
  138. 138.
    Fontes JD, Jabrane-Ferrat N, Toth CR, Peterlin BM: Binding and cooperative interactions between two B cell-specific transcriptional coactivators. J Exp Med 1996; 183:2517–2521.PubMedCrossRefGoogle Scholar
  139. 139.
    Scholl T, Mahanta SK, Strominger JL: Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5. Proc Natl Acad Sci USA 1997;94:6330–6334.PubMedCrossRefGoogle Scholar
  140. 140.
    Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, et al.: The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 1997;387:677–684.PubMedCrossRefGoogle Scholar
  141. 141.
    Egan KM, Seddon JM, Glynn RJ, Gragoudas ES, Albert DM: Epidemiologic aspects of uveal melanoma. Surv Ophthalmol 1988;32:239–251.PubMedCrossRefGoogle Scholar
  142. 142.
    Shammas HF, Blodi FC: Prognostic factors in choroidal and ciliary body melanomas. Arch Ophthalmol 1977;95:63–69.PubMedGoogle Scholar
  143. 143.
    Tucker MA, Shields JA, Hartge P, Augsburger J, Hoover RN, Fraumeni JF Jr.: Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med 1985;313:789–792.PubMedCrossRefGoogle Scholar
  144. 144.
    Barker CF, Billingham RE: Immunologically privileged sites. Adv Immunol 1977;25:1–54.PubMedGoogle Scholar
  145. 145.
    Streilein JW, Wilbanks GA, Cousims SW: Immunoregulatory mechanisms of the eye. J Neuroimmunol 1992;39:185–200.PubMedCrossRefGoogle Scholar
  146. 146.
    Streilein JW: Immunoregulatory mechanisms of the eye. Prog Retin Eye Res 1999;18:357–370.PubMedCrossRefGoogle Scholar
  147. 147.
    Reif OW, Freitag R: Studies of complexes between proteases, substrates and the protease inhibitor alpha 2-macroglobulin using capillary electrophoresis with laser-induced fluorescence detection. J Chromatogr A 1995; 716:363–369.PubMedCrossRefGoogle Scholar
  148. 148.
    Granstein RD, Staszewski R, Knisely TL, Zeira E, Nazareno R, Latira M, et al. Aqueous humor contains transforming growth factor-beta and a small (less than 3500 daltons) inhibitor of thymocyte proliferation. J Immunol 1990;144:3021–3027.PubMedGoogle Scholar
  149. 149.
    Cousins SW, McCabe MM, Danielpour D, Streilein JW: Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci 1991; 32:2201–2211.PubMedGoogle Scholar
  150. 150.
    Jampel HD, Roche N, Stark WJ, Roberts AB: Transforming growth factor-beta in human aqueous humor. Curr Eye Res 1990;9: 963–969.PubMedGoogle Scholar
  151. 151.
    Helbig H, Gurley RC, Palestine AG, Nussenblatt RB, Caspi RR: Dual effect of ciliary body cells on T lymphocyte proliferation. Eur J Immunol 1990;20:2457–2463.PubMedCrossRefGoogle Scholar
  152. 152.
    Knisely TL, Bleicber PA, Vibbard CA, Granstein RD: Production of latent transforming growth factor-beta and other inhibitory factors by cultured murine iris and ciliary body cells. Curr Eye Res 1991;10 761–771.PubMedGoogle Scholar
  153. 153.
    Takeuchi M, Alard P, Streilein JW: TGF-beta promotes immune deviation by altering accessory signals of antigen-presenting cells. J Immunol 1998;160: 1589–1597.PubMedGoogle Scholar
  154. 154.
    Takeuchi M, Kosiewicz MM, Alard P, Streilein JW: On the mechanisms by which transforming growth factor-beta 2 alters antigen-presenting abilities of macrophages on T cell activation. Eur J Immunol 1997;27:1648–1658.PubMedCrossRefGoogle Scholar
  155. 155.
    Taylor AW, Streilein JW, Cousins SW: Identification of alpha-melanocyte stimulating hormone as a potential immunosuppressive factor in aqueous humor. Curr Eye Res 1992;11:1199–1206.PubMedGoogle Scholar
  156. 156.
    Taylor AW, Alard P, Yee DG, Streilein JW: Aqueous humor induces transforming growth factor-beta (TGF-beta)-producing regulatory T-cells. Curr Eye Res 1997;16:900–908.PubMedCrossRefGoogle Scholar
  157. 157.
    Taylor AW, Streilein JW, Cousins SW: Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J Immunol 1994;153:108011086.Google Scholar
  158. 158.
    Ganea D, Sun L: Vasoactive intestinal peptide down regulates the expression of IL-2 but not of IFN gamma from stimulated murine T lymphocytes. J Neuroimmunol 1993;47:147–158.PubMedCrossRefGoogle Scholar
  159. 159.
    Ottaway CA: Vasoactive intestinal peptide as a modulator of lymphocyte and immune function. Ann NY Acad Sci 1988;527:486–500.PubMedCrossRefGoogle Scholar
  160. 160.
    Griffin AC, Zhao W, Wegmann KW, Hickley WF: Experimental autoimmune insulitis. Induction by T lymphocytes specific for a peptide of proinsulin. Am J Pathol 1995;147(3):845–857.PubMedGoogle Scholar
  161. 161.
    Yamagami S, Kawashima H, Tsuru T, Yamagami H, Kayagaki N, Yagita H, et al.: Role of Fas-Fas ligand interactions in the immuno-rejection of allogeneic mouse corneal transplants. Transplantation 1997;64:1107–1111.PubMedCrossRefGoogle Scholar
  162. 162.
    Stuart PM, Griffith TS, Usui N, Pepose J, Yu X, Ferguson TA: CD95 ligand (FasL)-inducedapoptosis is necessary for corneal allograft survival. J Clin Invest 1997; 99:396–402.PubMedCrossRefGoogle Scholar
  163. 163.
    Ono SJ, Bazil V, Sugawara M, Strominger JL: An isotype-specific trans-acting factor is defective in a mutant B cell line that expresses HLA-DQ, but not-DR or-DP. J Exp Med 1991;173:629–637.PubMedCrossRefGoogle Scholar
  164. 164.
    Ono SJ, Song Z: Mapping of the interaction site of the defective transcription factor in the class II major histocompatibility complex mutant cell line clone-13 to the divergent X2-box. J Biol Chem 1995;270:6396–6402.PubMedCrossRefGoogle Scholar
  165. 165.
    Chang CH, Guerder S, Hong SC, van Ewijk W, Flavell RA: Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity 1996;4: 167–178.PubMedCrossRefGoogle Scholar
  166. 166.
    Williams GS, Malin M, Vremec D, Chang CH, Boyd R, Benoist C, et al.: Mice lacking the transcription factor CIITA—a second look. Int Immunol 1998;10: 1957–1967.PubMedCrossRefGoogle Scholar
  167. 167.
    Collinge M, Pardi R, Bender JR: Class II transactivator-independent endothelial cell MHC class II gene activation induced by lymphocyte adhesion. J Immunol 1998;161: 1589–1593.PubMedGoogle Scholar
  168. 168.
    Gao J, De BP, Banerjee AK: Human parainfluenza virus type 3 upregulates major histocompatibility complex class I and II expression on respiratory epithelial cells: involvement of a STAT1-and CIITA-independent pathway. J Virol 1999;73:1411–1418.PubMedGoogle Scholar
  169. 169.
    Gao J, Choudhary S, Banerjee AK, De BP: Human parainfluenza virus type 3 upregulates ICAM-I (CD54) expression in a cytokine-independent manner. Gene Expr 2000;9:115–121.PubMedGoogle Scholar
  170. 170.
    Gao J., De BP, Han Y, Choudhary S, Ransohoff R, Banerjee AK: Human parainfluenza virus type 3 inhibits gamma interferon-induced major histocompatibility complex class II expression directly and by inducing alpha/beta interferon. J Virol 2001;75:1124–1131.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Michael Radosevich
    • 1
    • 2
  • Santa Jeremy Ono
    • 1
    • 2
  1. 1.Department of Immunology, Institute of OphthalmologyUniversity College London, University of LondonLondonUK
  2. 2.Committee on ImmunologyHarvard UniversityCambridge

Personalised recommendations