Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of MHC class II gene expression by the class II transactivator

Nature Reviews Immunology volume 5, pages 793–806 (2005)Cite this article

Key Points

  • MHC class II molecules are of central importance to the adaptive immune system. MHC-class-II-mediated peptide presentation is essential for positive and negative selection of CD4+ T cells in the thymus, for homeostasis of the mature CD4+ T-cell population in the periphery, and for the initiation, amplification and regulation of protective immune responses.

  • To fulfil their functions, MHC class II molecules must be expressed according to a precise cell-type-specific and quantitatively modulated pattern. Constitutive expression is largely restricted to thymic epithelial cells and antigen-presenting cells — that is, B cells, macrophages and dendritic cells (DCs) — whereas expression by other cell types requires induction by interferon-γ.

  • The key factor that controls almost all qualitative and quantitative aspects of MHC class II expression is the class II transactivator (CIITA), which is a non-DNA-binding co-activator.

  • Mutations in the CIITA gene cause a severe human immunodeficiency syndrome, which is known as bare lymphocyte syndrome. Gene-knockout mice carrying deletions of the corresponding mouse gene (C2ta) also show most features of the human disease.

  • The highly regulated pattern of expression of the gene encoding CIITA dictates where, when and to what level MHC class II genes are expressed. Transcription of the gene encoding CIITA is controlled by a large regulatory region that contains three independent promoters (pI, pIII and pIV). These have different well-defined functions that have been characterized in vivo by analysis of mice carrying targeted deletions of the C2ta promoters pIII and/or pIV.

  • The promoters pI and pIII share the job of driving CIITA expression in all antigen-presenting cells: pI is a myeloid-cell-specific promoter that is activated in macrophages and conventional DC subsets, whereas pIII is a lymphoid-cell-specific promoter that is essential for driving CIITA expression in B cells, activated human T cells and plasmacytoid DCs.

  • The promoter pIV is essential for driving CIITA expression in thymic epithelial cells (TECs) and in cells of non-haematopoietic origin that are stimulated with interferon-γ. Because MHC class II expression by cortical TECs drives positive selection of CD4+ T cells, pIV is essential for CD4+ T-cell development.

  • Dysregulated activation or repression of the promoters that drive the expression of CIITA is associated with various diseases, including infection with various pathogens, autoimmune and inflammatory diseases, and the development of tumours of various origins.

  • Detailed knowledge of the regulation and dysregulation of CIITA expression has set the stage for the development of novel therapeutic strategies aimed at modulating MHC-class-II-mediated antigen presentation.

Abstract

MHC class II molecules are pivotal for the adaptive immune system, because they guide the development and activation of CD4+ T helper cells. Fulfilling these functions requires that the genes encoding MHC class II molecules are transcribed according to a strict cell-type-specific and quantitatively modulated pattern. This complex gene-expression profile is controlled almost exclusively by a single master regulatory factor, which is known as the class II transactivator. As we discuss here, differential activation of the three independent promoters that drive expression of the gene encoding the class II transactivator ultimately determines the exquisitely regulated pattern of MHC class II gene expression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regulation of the transcription of MHC class II genes.
Figure 2: Modular structure of the regulatory region of the gene encoding CIITA.
Figure 3: Regulation of CIITA expression in health and disease.
Figure 4: Molecular regulation of pIII and pIV.

Similar content being viewed by others

References

  1. 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. 123, 921–928 (1993).

    CAS  PubMed  Google Scholar 

  2. Reith, W. & Mach, B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19, 331–373 (2001).

    CAS  PubMed  Google Scholar 

  3. Chang, C. H., Guerder, S., Hong, S. C., van Ewijk, W. & Flavell, R. A. Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity 4, 167–178 (1996). This paper, together with reference 5, describes the generation of C2ta -knockout mice, which have a global loss of MHC class II expression, thereby reproducing the phenotype of patients with BLS.

    CAS  PubMed  Google Scholar 

  4. Clausen, B. E. et al. Residual MHC class II expression on mature dendritic cells and activated B cells in RFX5-deficient mice. Immunity 8, 143–155 (1998).

    CAS  PubMed  Google Scholar 

  5. Itoh-Lindstrom, Y. et al. Reduced IL-4-, lipopolysaccharide-, and IFN-γ-induced MHC class II expression in mice lacking class II transactivator due to targeted deletion of the GTP-binding domain. J. Immunol. 163, 2425–2431 (1999).

    CAS  PubMed  Google Scholar 

  6. LeibundGut-Landmann, S., Waldburger, J. M., Reis e Sousa, C., Acha-Orbea, H. & Reith, W. MHC class II expression is differentially regulated in plasmacytoid and conventional dendritic cells. Nature Immunol. 5, 899–908 (2004). This paper describes the generation of mice that lack pIII and pIV of the C2ta gene and shows that pDCs differ from all other DC subsets with respect to C2ta promoter usage. The results define pI as a myeloid-cell-specific promoter and pIII as a lymphoid-cell-specific promoter.

    CAS  Google Scholar 

  7. Waldburger, J. M., Suter, T., Fontana, A., Acha-Orbea, H. & Reith, W. Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene. J. Exp. Med. 194, 393–406 (2001). This paper describes the generation of mice that lack pIV of the C2ta gene. It shows that this promoter is essential for driving IFN-γ-induced CIITA and MHC class II expression by non-haematopoietic cells but is dispensable for this function in macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ting, J. P. & Trowsdale, J. Genetic control of MHC class II expression. Cell 109, S21–S33 (2002).

    CAS  PubMed  Google Scholar 

  9. Boss, J. M. & Jensen, P. E. Transcriptional regulation of the MHC class II antigen presentation pathway. Curr. Opin. Immunol. 15, 105–111 (2003).

    CAS  PubMed  Google Scholar 

  10. LeibundGut-Landmann, S. et al. Specificity and expression of CIITA, the master regulator of MHCII genes. Eur. J. Immunol. 34, 1513–1525 (2004).

    CAS  PubMed  Google Scholar 

  11. Krawczyk, M. et al. Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA. J. Immunol. 173, 6200–6210 (2004).

    CAS  PubMed  Google Scholar 

  12. Masternak, K., Peyraud, N., Krawczyk, M., Barras, E. & Reith, W. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nature Immunol. 4, 132–137 (2003). References 11 and 12 show that CIITA is recruited not only to MHC class II promoters but also to multiple distant enhancers that are scattered throughout the MHC class II locus. One of these is situated in a locus control region that is found upstream of the HLA-DRA gene.

    CAS  Google Scholar 

  13. Accolla, R. S. Human B cell variants immunoselected against a single Ia antigen subset have lost expression in several Ia antigen subsets. J. Exp. Med. 157, 1053–1058 (1983).

    CAS  PubMed  Google Scholar 

  14. Accolla, R. S. et al. aIr-1, a newly found locus on mouse chromosome 16 encoding a trans-acting activator factor for MHC class II gene expression. J. Exp. Med. 164, 369–374 (1986).

    CAS  PubMed  Google Scholar 

  15. Steimle, V., Otten, L. A., Zufferey, M. & Mach, B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency. Cell 75, 135–146 (1993). This seminal work describes isolation of the gene encoding CIITA and shows that it is mutated in certain in vitro -generated MHC class II− cell lines and in patients with BLS who are classified in complementation group A.

    CAS  PubMed  Google Scholar 

  16. Steimle, V. et al. A novel DNA binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 9, 1021–1032 (1995).

    CAS  PubMed  Google Scholar 

  17. Masternak, K. et al. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nature Genet. 20, 273–277 (1998).

    CAS  PubMed  Google Scholar 

  18. Durand, B. et al. RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J. 16, 1045–1055 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Nagarajan, U. M. et al. RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity 10, 153–162 (1999). References 16–19 describe isolation of the genes encoding the RFXANK, RFX5 and RFXAP subunits of the RFX complex. They also show that these genes are mutated in patients with BLS who are classified in complementation group B, C and D, respectively.

    CAS  PubMed  Google Scholar 

  20. Reith, W. et al. Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X. Cell 53, 897–906 (1988).

    CAS  PubMed  Google Scholar 

  21. Moreno, C. S., Beresford, G. W., Louis-Plence, P., Morris, A. C. & Boss, J. M. CREB regulates MHC class II expression in a CIITA-dependent manner. Immunity 10, 143–151 (1999).

    CAS  PubMed  Google Scholar 

  22. Mantovani, R. The molecular biology of the CCAAT-binding factor NF-Y. Gene 239, 15–27 (1999).

    CAS  PubMed  Google Scholar 

  23. Muhlethaler-Mottet, A. et al. The S box of major histocompatibility complex class II promoters is a key determinant for recruitment of the transcriptional co-activator CIITA. J. Biol. Chem. 279, 40529–40535 (2004).

    CAS  PubMed  Google Scholar 

  24. Masternak, K. et al. CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex. Genes Dev. 14, 1156–1166 (2000). This paper was the first to show that CIITA is physically recruited to the promoters of its target genes in vivo and in vitro through multiple protein–protein interactions with an enhanceosome complex formed by DNA-bound transcription factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zika, E. & Ting, J. P. Epigenetic control of MHC class II: interplay between CIITA and histone-modifying enzymes. Curr. Opin. Immunol. 17, 58–64 (2005).

    CAS  PubMed  Google Scholar 

  26. Ting, J. P. & Davis, B. K. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu. Rev. Immunol. 23, 387–414 (2005).

    CAS  PubMed  Google Scholar 

  27. Inohara, N., Chamaillard, M., McDonald, C. & Nunez, G. NOD-LRR proteins: role in host–microbial interactions and inflammatory disease. Annu. Rev. Biochem. 74, 355–383 (2005).

    CAS  PubMed  Google Scholar 

  28. Fontes, J. D., Jiang, B. & Peterlin, B. M. The class II trans-activator CIITA interacts with the TBP-associated factor TAFII32. Nucleic Acids Res. 25, 2522–2528 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mahanta, S. K., Scholl, T., Yang, F. C. & Strominger, J. L. 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 94, 6324–6329 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Spilianakis, C. et al. CIITA regulates transcription onset via Ser5-phosphorylation of RNA Pol II. EMBO J. 22, 5125–5136 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kanazawa, S., Okamoto, T. & Peterlin, B. M. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 12, 61–70 (2000).

    CAS  PubMed  Google Scholar 

  32. Mudhasani, R. & Fontes, J. D. The class II transactivator requires brahma-related gene 1 to activate transcription of major histocompatibility complex class II genes. Mol. Cell. Biol. 22, 5019–5026 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Raval, A. et al. Transcriptional coactivator, CIITA, is an acetyltransferase that bypasses a promoter requirement for TAFII250. Mol. Cell 7, 105–115 (2001).

    CAS  PubMed  Google Scholar 

  34. Tosi, G., Jabrane-Ferrat, N. & Peterlin, B. M. Phosphorylation of CIITA directs its oligomerization, accumulation and increased activity on MHCII promoters. EMBO J. 21, 5467–5476 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sisk, T. J., Nickerson, K., Kwok, R. P. & Chang, C. H. Phosphorylation of class II transactivator regulates its interaction ability and transactivation function. Int. Immunol. 15, 1195–1205 (2003).

    CAS  PubMed  Google Scholar 

  36. Greer, S. F. et al. Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation. J. Immunol. 173, 376–383 (2004).

    CAS  PubMed  Google Scholar 

  37. Greer, S. F., Zika, E., Conti, B., Zhu, X. S. & Ting, J. P. Enhancement of CIITA transcriptional function by ubiquitin. Nature Immunol. 4, 1074–1082 (2003).

    CAS  Google Scholar 

  38. Waldburger, J. M. et al. Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells. Blood 101, 3550–3559 (2003). This paper shows that pIV of the C2ta gene is essential for driving positive selection of CD4+ T cells, because it is required for the induction of CIITA and MHC class II expression in TECs.

    CAS  PubMed  Google Scholar 

  39. Steimle, V., Siegrist, C.-A., Mottet, A., Lisowska-Grospierre, B. & Mach, B. Regulation of MHC class II expression by interferon-γ mediated by the transactivator gene CIITA. Science 265, 106–109 (1994). This seminal paper was the first to show that IFN-γ-induced MHC class II expression is mediated by the induction of CIITA expression.

    CAS  PubMed  Google Scholar 

  40. Dong, Y., Rohn, W. M. & Benveniste, E. N. IFN-γ regulation of the type IV class II transactivator promoter in astrocytes. J. Immunol. 162, 4731–4739 (1999).

    CAS  PubMed  Google Scholar 

  41. Muhlethaler-Mottet, A., Di Berardino, W., Otten, L. A. & Mach, B. Activation of the MHC class II transactivator CIITA by interferon-γ requires cooperative interaction between Stat1 and USF-1. Immunity 8, 157–166 (1998). This paper was the first detailed description of the molecular mechanisms that mediate the IFN-γ induction of pIV of CIITA.

    CAS  PubMed  Google Scholar 

  42. Muhlethaler-Mottet, A., Otten, L. A., Steimle, V. & Mach, B. Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. EMBO J. 16, 2851–2860 (1997). This key paper was the first to describe how multiple promoters with different functions drive transcription of the gene encoding CIITA.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. van den Elsen, P. J. et al. Lack of CIITA expression is central to the absence of antigen presentation functions of trophoblast cells and is caused by methylation of the IFN-γ inducible promoter (PIV) of CIITA. Hum. Immunol. 61, 850–862 (2000).

    CAS  PubMed  Google Scholar 

  44. Morris, A. C., Spangler, W. E. & Boss, J. M. Methylation of class II trans-activator promoter IV: a novel mechanism of MHC class II gene control. J. Immunol. 164, 4143–4149 (2000). References 43 and 44 report that the gene encoding CIITA is irreversibly silenced in trophoblasts by DNA methylation of pIV.

    CAS  PubMed  Google Scholar 

  45. 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 transactivator gene CIITA. J. Exp. Med. 180, 1329–1336 (1994).

    CAS  PubMed  Google Scholar 

  46. Sartoris, S., Tosi, G., De Lerma, B., Cestari, T. & Accolla, R. S. 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. 26, 2456–2460 (1996).

    CAS  PubMed  Google Scholar 

  47. Landmann, S. et al. Maturation of dendritic cells is accompanied by rapid transcriptional silencing of class II transactivator (CIITA) expression. J. Exp. Med. 194, 379–392 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Holling, T. M., Schooten, E., Langerak, A. W. & van den Elsen, P. J. Regulation of MHC class II expression in human T-cell malignancies. Blood 103, 1438–1444 (2004).

    CAS  PubMed  Google Scholar 

  49. Murphy, S. P., Holtz, R., Lewandowski, N., Tomasi, T. B. & Fuji, H. DNA alkylating agents alleviate silencing of class II transactivator gene expression in L1210 lymphoma cells. J. Immunol. 169, 3085–3093 (2002).

    CAS  PubMed  Google Scholar 

  50. van der Stoep, N., Biesta, P., Quinten, E. & van den Elsen, P. J. Lack of IFN-γ-mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines. Int. J. Cancer 97, 501–507 (2002).

    CAS  PubMed  Google Scholar 

  51. Lee, Y. J. et al. TGF-β suppresses IFN-γ induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression. J. Immunol. 158, 2065–2075 (1997).

    CAS  PubMed  Google Scholar 

  52. Rohn, W., Tang, L. P., Dong, Y. & Benveniste, E. N. IL-1β inhibits IFN-γ-induced class II MHC expression by suppressing transcription of the class II transactivator gene. J. Immunol. 162, 886–896 (1999).

    CAS  PubMed  Google Scholar 

  53. O'Keefe, G. M., Nguyen, V. T. & Benveniste, E. N. Class II transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-β, IL-4, IL-13 and IL-10. Eur. J. Immunol. 29, 1275–1285 (1999).

    CAS  PubMed  Google Scholar 

  54. Navarrete, S. A., Kehlen, A., Schutte, W., Langner, J. & Riemann, D. Regulation by transforming growth factor-β1 of class II mRNA and protein expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Int. Immunol. 10, 601–607 (1998).

    Google Scholar 

  55. Dong, Y., Tang, L., Letterio, J. J. & Benveniste, E. N. The Smad3 protein is involved in TGF-β inhibition of class II transactivator and class II MHC expression. J. Immunol. 167, 311–319 (2001).

    CAS  PubMed  Google Scholar 

  56. Okamoto, H., Asamitsu, K., Nishimura, H., Kamatani, N. & Okamoto, T. Reciprocal modulation of transcriptional activities between HIV-1 Tat and MHC class II transactivator CIITA. Biochem. Biophys. Res. Commun. 279, 494–499 (2000).

    CAS  PubMed  Google Scholar 

  57. Abendroth, A. et al. Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J. Virol. 74, 1900–1907 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Le Roy, E., Muhlethaler-Mottet, A., Davrinche, C., Mach, B. & Davignon, J. L. Escape of human cytomegalovirus from HLA-DR-restricted CD4+ T-cell response is mediated by repression of γ interferon-induced class II transactivator expression. J. Virol. 73, 6582–6589 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Miller, D. M. et al. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J. Exp. Med. 187, 675–683 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Gao, J. et al. Human parainfluenza virus type 3 inhibits γ interferon-induced major histocompatibility complex class II expression directly and by inducing α/β interferon. J. Virol. 75, 1124–1131 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhong, G., Fan, T. & Liu, L. Chlamydia inhibits interferon γ-inducible major histocompatibility complex class II expression by degradation of upstream stimulatory factor 1. J. Exp. Med. 189, 1931–1938 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Luder, C. G. et al. Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA. J. Neuroimmunol. 134, 12–24 (2003).

    CAS  PubMed  Google Scholar 

  63. Pai, R. K., Convery, M., Hamilton, T. A., Boom, W. H. & Harding, C. V. Inhibition of IFN-γ-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion. J. Immunol. 171, 175–184 (2003).

    CAS  PubMed  Google Scholar 

  64. Wojciechowski, W., DeSanctis, J., Skamene, E. & Radzioch, D. Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette–Guerin involves class II transactivator and depends on the Nramp1 gene. J. Immunol. 163, 2688–2696 (1999).

    CAS  PubMed  Google Scholar 

  65. Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Statins as a newly recognized type of immunomodulator. Nature Med. 6, 1399–1402 (2000).

    CAS  PubMed  Google Scholar 

  66. Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a TH2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78–84 (2002).

    CAS  PubMed  Google Scholar 

  67. De Lerma, B. A., Procopio, F. A., Mortara, L., Tosi, G. & Accolla, R. S. The MHC class II transactivator (CIITA) mRNA stability is critical for the HLA class II gene expression in myelomonocytic cells. Eur. J. Immunol. 35, 603–611 (2005).

    Google Scholar 

  68. Schnappauf, F. et al. N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA. Eur. J. Immunol. 33, 2337–2347 (2003).

    CAS  PubMed  Google Scholar 

  69. Nickerson, K. et al. Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity. J. Biol. Chem. 276, 19089–19093 (2001).

    CAS  PubMed  Google Scholar 

  70. Deffrennes, V. et al. Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter. J. Immunol. 167, 98–106 (2001).

    CAS  PubMed  Google Scholar 

  71. Goodwin, B. L. et al. Varying functions of specific major histocompatibility class II transactivator promoter III and IV elements in melanoma cell lines. Cell Growth Differ. 12, 327–335 (2001).

    CAS  PubMed  Google Scholar 

  72. Piskurich, J. F., Linhoff, M. W., Wang, Y. & Ting, J. P. Two distinct γ 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 β. Mol. Cell. Biol. 19, 431–440 (1999). This paper shows that pIII of the human CIITA gene can be induced by IFN-γ through a STAT1-dependent enhancer that is situated 5 kb upstream.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Suter, T. 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. 30, 794–802 (2000).

    CAS  PubMed  Google Scholar 

  74. Pai, R. K., Askew, D., Boom, W. H. & Harding, C. V. Regulation of class II MHC expression in APCs: roles of types I, III, and IV class II transactivator. J. Immunol. 169, 1326–1333 (2002). Together with reference 6, this detailed kinetic study of CIITA expression shows that transcription from pI is sustained in IFN-γ-stimulated macrophages, whereas pIV is induced only transiently.

    CAS  PubMed  Google Scholar 

  75. O'Keefe, G. M., Nguyen, V. T., Ping Tang, L. L. & Benveniste, E. N. IFN-γ regulation of class II transactivator promoter IV in macrophages and microglia: involvement of the suppressors of cytokine signaling-1 protein. J. Immunol. 166, 2260–2269 (2001).

    CAS  PubMed  Google Scholar 

  76. Nikcevich, K. M., Piskurich, J. F., Hellendall, R. P., Wang, Y. & Ting, J. P. Differential selectivity of CIITA promoter activation by IFN-γ and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affected by TNF-α. J. Neuroimmunol. 99, 195–204 (1999).

    CAS  PubMed  Google Scholar 

  77. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    CAS  PubMed  Google Scholar 

  78. Martinic, M. M. et al. Efficient T cell repertoire selection in tetraparental chimeric mice independent of thymic epithelial MHC. Proc. Natl Acad. Sci. USA 100, 1861–1866 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Xi, H. et al. Co-occupancy of the interferon regulatory element of the class II transactivator (CIITA) type IV promoter by interferon regulatory factors 1 and 2. Oncogene 18, 5889–5903 (1999).

    CAS  PubMed  Google Scholar 

  80. Xi, H., Goodwin, B., Shepherd, A. T. & Blanck, G. Impaired class II transactivator expression in mice lacking interferon regulatory factor-2. Oncogene 20, 4219–4227 (2001).

    CAS  PubMed  Google Scholar 

  81. Morris, A. C., Beresford, G. W., Mooney, M. R. & Boss, J. M. Kinetics of a γ interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Mol. Cell. Biol. 22, 4781–4791 (2002). This paper reports a detailed time course of the events that lead to the activation of pIV by IFN-γ.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Takeuchi, O. et al. Differential usage of class II transactivator promoters PI and PIV during inflammation and injury in kidney. J. Am. Soc. Nephrol. 14, 2823–2832 (2003).

    CAS  PubMed  Google Scholar 

  83. Pattenden, S. G., Klose, R., Karaskov, E. & Bremner, R. Interferon-γ-induced chromatin remodeling at the CIITA locus is BRG1 dependent. EMBO J. 21, 1978–1986 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Holtz, R., Choi, J. C., Petroff, M. G., Piskurich, J. F. & Murphy, S. P. Class II transactivator (CIITA) promoter methylation does not correlate with silencing of CIITA transcription in trophoblasts. Biol. Reprod. 69, 915–924 (2003).

    CAS  PubMed  Google Scholar 

  85. Murphy, S. P., Choi, J. C. & Holtz, R. Regulation of major histocompatibility complex class II gene expression in trophoblast cells. Reprod. Biol. Endocrinol. 2, 52 (2004).

    PubMed  PubMed Central  Google Scholar 

  86. Anderson, G., Jenkinson, E. J., Moore, N. C. & Owen, J. J. MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362, 70–73 (1993).

    CAS  PubMed  Google Scholar 

  87. Anderson, G. & Jenkinson, E. J. Lymphostromal interactions in thymic development and function. Nature Rev. Immunol. 1, 31–40 (2001).

    CAS  Google Scholar 

  88. Anderson, G., Hare, K. J., Platt, N. & Jenkinson, E. J. Discrimination between maintenance- and differentiation-inducing signals during initial and intermediate stages of positive selection. Eur. J. Immunol. 27, 1838–1842 (1997).

    CAS  PubMed  Google Scholar 

  89. Honey, K. & Rudensky, A. The pIV-otal class II transactivator promoter regulates major histocompatibility complex class II expression in the thymus. J. Exp. Med. 194, F15–F18 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Rigaud, G. et al. Induction of CIITA and modification of in vivo HLA-DR promoter occupancy in normal thymic epithelial cells treated with IFN-γ: similarities and distinctions with respect to HLA-DR-constitutive B cells. J. Immunol. 156, 4254–4258 (1996).

    CAS  PubMed  Google Scholar 

  91. Hare, K. J., Jenkinson, E. J. & Anderson, G. In vitro models of T cell development. Semin. Immunol. 11, 3–12 (1999).

    CAS  PubMed  Google Scholar 

  92. Dalton, D. K. et al. Multiple defects of immune cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993).

    CAS  PubMed  Google Scholar 

  93. Huang, S. et al. Immune response in mice that lack the interferon-γ receptor. Science 259, 1742–1745 (1993).

    CAS  PubMed  Google Scholar 

  94. Gill, J. et al. Thymic generation and regeneration. Immunol. Rev. 195, 28–50 (2003).

    CAS  PubMed  Google Scholar 

  95. Lennon, A. M. et al. Isolation of a B-cell-specific promoter for the human class II transactivator. Immunogenetics 45, 266–273 (1997).

    CAS  PubMed  Google Scholar 

  96. Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nature Immunol. 5, 1219–1226 (2004).

    CAS  Google Scholar 

  97. Otten, L. A. et al. Deregulated MHC class II transactivator expression leads to a strong TH2 bias in CD4+ T lymphocytes. J. Immunol. 170, 1150–1157 (2003).

    CAS  PubMed  Google Scholar 

  98. Holling, T. M., van der Stoep, N., Quinten, E. & van den Elsen, P. J. Activated human T cells accomplish MHC class II expression through T cell-specific occupation of class II transactivator promoter III. J. Immunol. 168, 763–770 (2002).

    CAS  PubMed  Google Scholar 

  99. Wong, A. W. et al. Regulation and specificity of MHC2TA promoter usage in human primary T lymphocytes and cell line. J. Immunol. 169, 3112–3119 (2002). References 98 and 99 establish that pIII of the CIITA gene drives CIITA and MHC class II expression by human T cells.

    CAS  PubMed  Google Scholar 

  100. Ghosh, N. et al. A novel element and a TEF-2-like element activate the major histocompatibility complex class II transactivator in B-lymphocytes. J. Biol. Chem. 274, 32342–32350 (1999).

    CAS  PubMed  Google Scholar 

  101. van der Stoep, N., Quinten, E. & van den Elsen, P. J. Transcriptional regulation of the MHC class II trans-activator (CIITA) promoter III: identification of a novel regulatory region in the 5′-untranslated region and an important role for cAMP-responsive element binding protein 1 and activating transcription factor-1 in CIITA-promoter III transcriptional activation in B lymphocytes. J. Immunol. 169, 5061–5071 (2002).

    PubMed  Google Scholar 

  102. van der Stoep, N., Quinten, E., Marcondes, R. M. & van den Elsen, P. J. E47, IRF-4, and PU.1 synergize to induce B-cell-specific activation of the class II transactivator promoter III (CIITA-PIII). Blood 104, 2849–2857 (2004). This paper shows that the B-cell-specific activity of pIII of the CIITA gene can be attributed to binding of the transcription factors E47, IRF4 and PU.1.

    CAS  PubMed  Google Scholar 

  103. Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nature Genet. 37, 486–494 (2005).

    CAS  PubMed  Google Scholar 

  104. Piskurich, J. F. et al. BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nature Immunol. 1, 526–532 (2000).

    CAS  Google Scholar 

  105. Ghosh, N., Gyory, I., Wright, G., Wood, J. & Wright, K. L. Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells. J. Biol. Chem. 276, 15264–15268 (2001).

    CAS  PubMed  Google Scholar 

  106. Accolla, R. S., Mazza, S., De Lerma, B. A., De, M. A. & Tosi, G. The HLA class II transcriptional activator blocks the function of HIV-1 Tat and inhibits viral replication. Eur. J. Immunol. 32, 2783–2791 (2002).

    CAS  PubMed  Google Scholar 

  107. Casoli, C. et al. The MHC class II transcriptional activator (CIITA) inhibits HTLV-2 viral replication by blocking the function of the viral transactivator Tax-2. Blood 103, 995–1001 (2004).

    CAS  PubMed  Google Scholar 

  108. Garcia-Lora, A., Algarra, I., Collado, A. & Garrido, F. Tumour immunology, vaccination and escape strategies. Eur. J. Immunogenet. 30, 177–183 (2003).

    CAS  PubMed  Google Scholar 

  109. Toes, R. E., Schoenberger, S. P., van der Voort, E. I., Offringa, R. & Melief, C. J. CD40–CD40Ligand interactions and their role in cytotoxic T lymphocyte priming and anti-tumor immunity. Semin. Immunol. 10, 443–448 (1998).

    CAS  PubMed  Google Scholar 

  110. Liu, A. et al. Regulation of the expression of MHC class I and II by class II transactivator (CIITA) in hematopoietic cells. Hematol. Oncol. 17, 149–160 (1999).

    PubMed  Google Scholar 

  111. Momburg, F., Herrmann, B., Moldenhauer, G. & Moller, P. B-cell lymphomas of high-grade malignancy frequently lack HLA-DR, -DP and -DQ antigens and associated invariant chain. Int. J. Cancer 40, 598–603 (1987).

    CAS  PubMed  Google Scholar 

  112. Rimsza, L. M. et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 103, 4251–4258 (2004).

    CAS  PubMed  Google Scholar 

  113. Fuji, H. & Iribe, H. Clonal variation in tumorigenicity of L1210 lymphoma cells: nontumorigenic variants with an enhanced expression of tumor-associated antigen and Ia antigens. Cancer Res. 46, 5541–5547 (1986).

    CAS  PubMed  Google Scholar 

  114. Altomonte, M., Fonsatti, E., Visintin, A. & Maio, M. Targeted therapy of solid malignancies via HLA class II antigens: a new biotherapeutic approach? Oncogene 22, 6564–6569 (2003).

    CAS  PubMed  Google Scholar 

  115. Morimoto, Y. et al. Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells. Br. J. Cancer 90, 844–852 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cook, G. & Campbell, J. D. Immune regulation in multiple myeloma: the host–tumour conflict. Blood Rev. 13, 151–162 (1999).

    CAS  PubMed  Google Scholar 

  117. Takamura, Y. et al. Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA). Glia 45, 392–405 (2004).

    PubMed  Google Scholar 

  118. Guardiola, J. & Maffei, A. Control of MHC class II gene expression in autoimmune, infectious, and neoplastic diseases. Crit. Rev. Immunol. 13, 247–268 (1993).

    CAS  PubMed  Google Scholar 

  119. Li, S., Kurts, C., Kontgen, F., Holdsworth, S. R. & Tipping, P. G. Major histocompatibility complex class II expression by intrinsic renal cells is required for crescentic glomerulonephritis. J. Exp. Med. 188, 597–602 (1998). This paper provides convincing evidence that MHC class II expression in renal tissues is required for the development of experimental glomerulonephritis in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Leung, B. P. et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J. Immunol. 170, 1524–1530 (2003).

    CAS  PubMed  Google Scholar 

  121. Palmer, G. et al. Assessment of the efficacy of different statins in murine collagen-induced arthritis. Arthritis Rheum. 50, 4051–4059 (2004).

    CAS  PubMed  Google Scholar 

  122. McCarey, D. W. et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363, 2015–2021 (2004).

    CAS  PubMed  Google Scholar 

  123. Kuipers, H. F. & van den Elsen, P. J. Statins and control of MHC2TA gene transcription. Nature Med. 11, 365–366 (2005).

    CAS  PubMed  Google Scholar 

  124. Martin, B. K., Frelinger, J. G. & Ting, J. P. Combination gene therapy with CD86 and the MHC class II transactivator in the control of lung tumor growth. J. Immunol. 162, 6663–6670 (1999).

    CAS  PubMed  Google Scholar 

  125. Meazza, R., Comes, A., Orengo, A. M., Ferrini, S. & Accolla, R. S. Tumor rejection by gene transfer of the MHC class II transactivator in murine mammary adenocarcinoma cells. Eur. J. Immunol. 33, 1183–1192 (2003).

    CAS  PubMed  Google Scholar 

  126. Hillman, G. G. et al. Generating MHC class II+/Ii− phenotype after adenoviral delivery of both an expressible gene for MHC class II inducer and an antisense Ii-RNA construct in tumor cells. Gene Ther. 10, 1512–1518 (2003).

    CAS  PubMed  Google Scholar 

  127. Clements, V. K., Baskar, S., Armstrong, T. D. & Ostrand-Rosenberg, S. Invariant chain alters the malignant phenotype of MHC class II+ tumor cells. J. Immunol. 149, 2391–2396 (1992).

    CAS  PubMed  Google Scholar 

  128. Dissanayake, S. K., Tuera, N. & Ostrand-Rosenberg, S. Presentation of endogenously synthesized MHC class II-restricted epitopes by MHC class II cancer vaccines is independent of transporter associated with Ag processing and the proteasome. J. Immunol. 174, 1811–1819 (2005).

    CAS  PubMed  Google Scholar 

  129. Wang, Y. et al. Curative antitumor immune response is optimal with tumor irradiation followed by genetic induction of major histocompatibility complex class I and class II molecules and suppression of Ii protein. Hum. Gene Ther. 16, 187–199 (2005). This paper describes a mouse model of prostate cancer in which 50% of the mice were cured by combining radiotherapy with gene therapy using CIITA, IFN-γ and IL-2 expression vectors, together with an antisense construct directed towards Ii mRNA. Moreover, 100% of cured animals were resistant to rechallenge with tumour cells.

    CAS  PubMed  Google Scholar 

  130. Nagy, Z. A. et al. Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. Nature Med. 8, 801–807 (2002).

    CAS  PubMed  Google Scholar 

  131. Dechant, M., Bruenke, J. & Valerius, T. HLA class II antibodies in the treatment of hematologic malignancies. Semin. Oncol. 30, 465–475 (2003).

    CAS  PubMed  Google Scholar 

  132. Martin, B. K. et al. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 6, 591–600 (1997).

    CAS  PubMed  Google Scholar 

  133. Gobin, S. J., Peijnenburg, A., Keijsers, V. & van den Elsen, P. J. Site α is crucial for two routes of IFN γ-induced MHC class I transactivation: the ISRE-mediated route and a novel pathway involving CIITA. Immunity 6, 601–611 (1997).

    CAS  PubMed  Google Scholar 

  134. Wong, A. W. et al. CIITA-regulated plexin-A1 affects T-cell–dendritic cell interactions. Nature Immunol. 4, 891–898 (2003).

    CAS  Google Scholar 

  135. Nagarajan, U. M., Bushey, A. & Boss, J. M. Modulation of gene expression by the MHC class II transactivator. J. Immunol. 169, 5078–5088 (2002).

    PubMed  Google Scholar 

  136. Zhu, X. S. & Ting, J. P. A 36-amino-acid region of CIITA is an effective inhibitor of CBP: novel mechanism of γ interferon-mediated suppression of collagen α2(I) and other promoters. Mol. Cell. Biol. 21, 7078–7088 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Yee, C. S. et al. Cathepsin E: a novel target for regulation by class II transactivator. J. Immunol. 172, 5528–5534 (2004).

    CAS  PubMed  Google Scholar 

  138. Gourley, T. S., Patel, D. R., Nickerson, K., Hong, S. C. & Chang, C. H. Aberrant expression of Fas ligand in mice deficient for the MHC class II transactivator. J. Immunol. 168, 4414–4419 (2002).

    CAS  PubMed  Google Scholar 

  139. Sisk, T. J., Gourley, T., Roys, S. & Chang, C. H. MHC class II transactivator inhibits IL-4 gene transcription by competing with NF-AT to bind the coactivator CREB binding protein (CBP)/p300. J. Immunol. 165, 2511–2517 (2000).

    CAS  PubMed  Google Scholar 

  140. Park, W. S. et al. T cell expression of CIITA represses TH1 immunity. Int. Immunol. 16, 1355–1364 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to B. Mach, in whose laboratory this subject was first initiated. We are also grateful to all current and past members of our laboratories, particularly B. Durand, M. Krawczyk, K. Masternak, A. Muhlethaler-Mottet, L. Otten and V. Steimle, who made pivotal contributions to the field. We thank H. Acha-Orbea, A. Fontana and C. Reis e Sousa for important collaborations. Work in our laboratory was supported by the Swiss National Science Foundation, the Roche Research Foundation (Switzerland), the Gabriella Giorgi-Cavaglieri Foundation (Switzerland), the Ernst and Lucie Schmidheiny Foundation (Switzerland), the Swiss Multiple Sclerosis Society and the National Center of Competence in Research on Neural Plasticity and Repair (Switzerland).

Author information

Authors and Affiliations

  1. Department of Pathology and Immunology, University of Geneva Medical School, Centre Médical Universitaire, 1 Rue Michel-Servet, Geneva, CH-1211, Switzerland

    Walter Reith, Salomé LeibundGut-Landmann & Jean-Marc Waldburger

  2. Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Salomé LeibundGut-Landmann

Authors
  1. Walter Reith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salomé LeibundGut-Landmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Marc Waldburger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Walter Reith.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

CIITA

CREB

E47

IFN-γ

IRF1

IRF2

IRF4

NFY

P-TEFb

PU.1

RFX5

RFXANK

RFXAP

TFIIB

TFIID

USF1

OMIM

bare lymphocyte syndrome

FURTHER INFORMATION

Walter Reith's homepage

Glossary

ASTROCYTE

A star-shaped glial cell of the central-nervous system that forms a structural and functional interface between non-nervous tissues and neurons.

TROPHOBLAST

A cell of the outer layer of the mammalian blastocyst that gives rise to the embryonic portion of the placenta.

ENHANCER

A composite regulatory region that is composed of several distinct sequence elements that are bound by sequence-specific transcription factors that act positively or negatively on the transcription of an adjacent gene.

REGULATORY-FACTOR-X FAMILY

(RFX family). A family of evolutionarily related DNA-binding proteins that has diverse functions in eukaryotic organisms, ranging from yeast to man. There are five family members (RFX1, RFX2, RFX3, RFX4 and RFX5) in mammals.

CHROMATIN MODIFICATION

Alterations that are induced in chromatin by enzymes that modify the extent of acetylation, methylation or other covalent modifications of histones.

GENERAL TRANSCRIPTION MACHINERY

Factors that are required for the initiation of transcription of all genes that are transcribed by RNA polymerase II. They include RNA polymerase II itself and numerous general transcription factors that assemble at the core promoter (that is, the DNA sequence that surrounds the transcription-initiation site) of these genes.

CHROMATIN REMODELLING

Alterations that are induced in chromatin through the displacement of nucleosomes by ATP-dependent multiprotein complexes.

BRAHMA-RELATED GENE 1

(BRG1). An ATPase subunit that is present in chromatin-remodelling complexes that are known as SWI–SNF (switching-defective–sucrose non-fermenting) complexes.

MICROGLIA

Small glial cells that are distributed throughout the grey and white matter in the central-nervous system. They are monocyte-derived cells that invade neural tissue before birth and can differentiate into macrophages.

FIBROSARCOMA

A malignant tumour that is derived from connective-tissue fibroblasts.

REAGGREGATE THYMIC ORGAN CULTURE

Three-dimensional thymus-lobe structures that are formed in cell culture by the reaggregation of cells that are present in mixtures of purified thymocytes and thymic stromal-cell subsets.

T-CELL-DEPENDENT ANTIGEN

CD4+ T-cell help is required for the production of high-affinity antibodies specific for this type of antigen.

PLASMACYTOID DC

(pDC). A unique type of dendritic cell (DC). These cells are also known as interferon (IFN)-producing cells because they are the main source of type I IFNs (that is, IFN-α and IFN-β) during viral infections.

GLIOBLASTOMA

A malignant tumour that is derived from glial cells.

GLOMERULONEPHRITIS

An inflammation of the kidney glomeruli that can result in destruction of the glomeruli and renal failure.

STATINS

A family of inhibitors of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyses the conversion of HMG-CoA to L-mevalonate. These molecules are mainly used as cholesterol-lowering drugs, but they also have immunoregulatory and anti-inflammatory properties. L-Mevalonate and its metabolites are implicated in cholesterol synthesis and other intracellular pathways.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

COLLAGEN-INDUCED ARTHRITIS

(CIA). An experimental model of rheumatoid arthritis that is induced by immunization of susceptible animals with collagen type II.

DNA-ALKYLATING AGENT

An anticancer drug that is cytotoxic to rapidly proliferating cells because it leads to the alkylation of bases in DNA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reith, W., LeibundGut-Landmann, S. & Waldburger, JM. Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol 5, 793–806 (2005). https://doi.org/10.1038/nri1708

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1708

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing