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.

  • Original Manuscript
  • Published:

Defective class II transactivator expression in a B lymphoma cell line

Leukemia volume 18, pages 832–840 (2004)Cite this article

Abstract

Loss of MHC class II expression in B-cell lymphoma has been associated with a higher tumorigenicity resulting from lower titers of tumor-infiltrating lymphocytes. This report aims towards the identification of the molecular mechanism leading to defective MHC class II expression in a B-cell lymphoma cell line, Rec-1. We evidenced a coordinated alteration of HLA-D gene transcription, reminiscent of B lymphoblastoid cell lines from patients with MHC class II deficiency. Genetic complementation performed between these cell lines and the lymphoma cells indicated that Rec-1 is altered in the MHC2TA gene. MHC2TA encodes the class II transactivator (CIITA), the master regulator of HLA-D gene expression. However, the coding sequence of the Rec-1 CIITA transcript did not reveal any mutation that could hamper the activity of the encoded protein. In agreement with the genetic complementation analysis, we evidenced a highly residual CIITA protein expression in the Rec-1 cell line resulting from a transcriptional defect affecting MHC2TA expression. Anti-HLA-DR monoclonal antibody treatment has proved efficient in the destruction of B lymphoma cells. Our data indicate that the appearance of variants losing CIITA, and thereby HLA-DR, expression will require a thorough monitoring during such immunotherapy protocols.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Germain RN . MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994; 76: 287–299.

    Article  CAS  PubMed  Google Scholar 

  2. Glimcher LH, Kara CJ . Sequences and factors: a guide to MHC class II transcription. Ann Rev Immunol 1992; 10: 13–50.

    Article  CAS  Google Scholar 

  3. Reith W, Muhlethaler-Mottet A, Masternak K, Villard J, Mach B . The molecular basis of MHC class II deficiency and transcriptional control of MHC class II gene expression. Microbes Infect 1999; 1: 839–846.

    Article  CAS  PubMed  Google Scholar 

  4. Reith W, Mach B . The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 2001; 19: 331–373.

    Article  CAS  PubMed  Google Scholar 

  5. Harton JA, Ting JP . Class II transactivator: mastering the art of major histocompatibility complex expression. Mol Cell Biol 2000; 20: 6185–6194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Steimle V, Otten LA, Zufferey M, Mach B . Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 1993; 75: 135–146.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Spilianakis C, Papamatheakis J, Kretsovali A . Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol Cell Biol 2000; 20: 8489–8498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. Chang CH, Fontes JD, Peterlin M, Flavell RA . Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes. J Exp Med 1994; 180: 1367–1374.

    Article  CAS  PubMed  Google Scholar 

  14. Muhlethaler-Mottet A, Otten LA, 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 1997; 16: 2851–2860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Barbieri G, Deffrennes V, Prod'homme T, Vedrenne J, Baton F, Cortes C et al. Isoforms of the class II transactivator protein. Int Immunol 2002; 14: 839–848.

    Article  CAS  PubMed  Google Scholar 

  17. Nickerson K, Sisk TJ, Inohara N, Yee CS, Kennell J, Cho MC et al. Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity. J Biol Chem 2001; 276: 19089–19093.

    Article  CAS  PubMed  Google Scholar 

  18. Griscelli C, Lisowska-Grospierre B, Mach B . Combined immunodeficiency with defective expression in MHC class II genes. Immunodeficiency Rev 1989; 1: 135–143.

    CAS  Google Scholar 

  19. Benichou B, Strominger JL et al. Class II-antigen-negative patient and mutant B-cell lines represent at least three, and probably four, distinct genetic defects defined by complementation analysis. Proc Natl Acad Sci USA 1991; 88: 4285–4288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 II deficiency patients. Nat Genet 1998; 20: 273–277.

    Article  CAS  PubMed  Google Scholar 

  21. Steimle V, Durand B, Barras E, Zufferey M, Hadam MR, Mach B et al. A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev 1995; 9: 1021–1032.

    Article  CAS  PubMed  Google Scholar 

  22. 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 II deficiency. EMBO J. 1997; 16: 1045–1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dziembowska M, Fondaneche MC, Vedrenne J, Barbieri G, Wiszniewski W, Picard C et al. Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenetics 2002; 53: 821–829.

    Article  CAS  PubMed  Google Scholar 

  24. Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H et al. Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 1999; 187: 191–199.

    Article  CAS  PubMed  Google Scholar 

  25. Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C et al. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol 2000; 165: 7017–7024.

    Article  CAS  PubMed  Google Scholar 

  26. Lu Y, Tschickardt ME, Schmidt BJ, Blanck G . IFN-gamma inducibility of class II transactivator is specifically lacking in human tumour lines: relevance to retinoblastoma protein rescue of IFN-gamma inducibility of the HLA class II genes. Immunol Cell Biol 1997; 75: 325–332.

    Article  CAS  PubMed  Google Scholar 

  27. Xi H, Blanck G . Interferon regulatory factor-2 point mutations in human pancreatic tumors. Int J Cancer 2000; 87: 803–808.

    Article  CAS  PubMed  Google Scholar 

  28. Naves R, Lennon AM, Barbieri G, Reyes L, Puga G, Salas L et al. MHC class II-deficient tumor cell lines with a defective expression of the class II transactivator. Int Immunol 2002; 14: 481–491.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Stopeck AT, Gessner A, Miller TP, Hersh EM, Johnson CS, Cui H et al. Loss of B7.2 (CD86) and intracellular adhesion molecule 1 (CD54) expression is associated with decreased tumor-infiltrating T lymphocytes in diffuse B-cell large-cell lymphoma. Clin Cancer Res 2000; 6: 3904–3909.

    CAS  PubMed  Google Scholar 

  31. Amiot L, Onno M, Lamy T, Dauriac C, Le Prise PY, Fauchet R et al. Loss of HLA molecules in B lymphomas is associated with an aggressive clinical course. Br J Haematol 1998; 100: 655–663.

    Article  CAS  PubMed  Google Scholar 

  32. 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 1986; 46: 5541–5547.

    CAS  PubMed  Google Scholar 

  33. Coiffier B, Gisselbrecht C, Herbrecht R, Tilly H, Bosly A, Brousse N . LNH-84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma. J Clin Oncol 1989; 7: 1018–1026.

    Article  CAS  PubMed  Google Scholar 

  34. Meeker TC, Sellers W, Harvey R, Withers D, Carey K, Xiao H et al. Cloning of the t(11;14)(q13;q32) translocation breakpoints from two human leukemia cell lines. Leukemia 1991; 5: 733–737.

    CAS  PubMed  Google Scholar 

  35. Brown JA, He XF, Westerheide SD, Boss JM . Characterization of the expressed CIITA allele in the class II MHC transcriptional mutant RJ2.2.5. Immunogenetics 1996; 43: 88–91.

    CAS  PubMed  Google Scholar 

  36. Lisowska-Grospierre B, Fondaneche M-C, Rois M-P, Griscelli C, Fischer A . Two complementation groups account for most cases in inherited MHC class II deficiency. Hum Mol Genet 1994; 3: 953–958.

    Article  CAS  PubMed  Google Scholar 

  37. Watson AJ, DeMars R, Trowbridge IS, Bach FH . Detection of a novel human class II HLA antigen. Nature 1983; 304: 358–361.

    Article  CAS  PubMed  Google Scholar 

  38. Lennon A, Ottone C, Peijnenburg A, Hamon-Benais C, Colland F, Gobin S et al. The RAG cell line defines a new complementation group of MHC class II deficiency. Immunogenetics 1996; 43: 352–359.

    Article  CAS  PubMed  Google Scholar 

  39. Zhou H, Su HS, Zhang X, Douhan III J, Glimcher LH . CIITA-dependent and -independent class II MHC expression revealed by a dominant negative mutant. J Immunol 1997; 158: 4741–4749.

    CAS  PubMed  Google Scholar 

  40. 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: 921–929.

    Article  CAS  PubMed  Google Scholar 

  41. Piskurich JF, Lin KI, Lin Y, Wang Y, Ting JP, Calame K . BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat Immunol 2000; 1: 526–532.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. Peijnenburg A, Van den Berg R, Van Eggermond MJ, Sanal O, Vossen JM, Lennon AM et al. Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene. Immunogenetics 2000; 51: 42–49.

    Article  CAS  PubMed  Google Scholar 

  44. Nagarajan UM, Bushey A, Boss JM . Modulation of gene expression by the MHC class II transactivator. J Immunol 2002; 169: 5078–5088.

    Article  PubMed  Google Scholar 

  45. Wakasugi K, Slike BM, Hood J, Ewalt KL, Cheresh DA, Schimmel P . Induction of angiogenesis by a fragment of human tyrosyl-tRNA synthetase. J Biol Chem 2002; 277: 20124–20136.

    Article  CAS  PubMed  Google Scholar 

  46. Choy L, Derynck R . The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response. J Biol Chem. 1998; 273: 31455–31462.

    Article  CAS  PubMed  Google Scholar 

  47. Murphy SP, Holtz R, Lewandowski N, Tomasi TB, Fuji H . DNA Alkylating agents alleviate silencing of class II transactivator gene expression in L1210 lymphoma cells. J Immunol 2002; 169: 3085–3093.

    Article  CAS  PubMed  Google Scholar 

  48. Wiszniewski W, Fondaneche MC, Le Deist F, Kanariou M, Selz F, Brousse N et al. Mutation in the class II trans-activator leading to a mild immunodeficiency. J Immunol 2001; 167: 1787–1794.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. Otten LA, Tacchini-Cottier F, Lohoff M, Annunziato F, Cosmi L, Scarpellino L et al. Deregulated MHC class II transactivator expression leads to a strong Th2 bias in CD4+ T lymphocytes. J Immunol 2003; 170: 1150–1157.

    Article  CAS  PubMed  Google Scholar 

  51. Zhu XS, Ting JP . A 36-amino-acid region of CIITA is an effective inhibitor of CBP: novel mechanism of gamma interferon-mediated suppression of collagen alpha(2)(I) and other promoters. Mol Cell Biol 2001; 21: 7078–7088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chan HM, La Thangue NB . p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci 2001; 114: 2363–2373.

    CAS  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. Chiari R, Hames G, Stroobant V, Texier C, Maillere B, Boon T et al. Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules. Cancer Res 2000; 60: 4855–4863.

    CAS  PubMed  Google Scholar 

  55. Drenou B, Blancheteau V, Burgess DH, Fauchet R, Charron DJ, Mooney NA . A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes. J Immunol 1999; 163: 4115–4124.

    CAS  PubMed  Google Scholar 

  56. Dechant M, Bruenke J, Valerius T . HLA class II antibodies in the treatment of hematologic malignancies. Semin Oncol 2003; 30: 465–475.

    Article  CAS  PubMed  Google Scholar 

  57. Nagy ZA, Hubner B, Lohning C, Rauchenberger R, Reiffert S, Thomassen-Wolf E et al. Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. Nat Med 2002; 8: 801–807.

    Article  CAS  PubMed  Google Scholar 

  58. Kosmas C, Stamatopoulos K, Stavroyianni N, Tsavaris N, Papadaki T . Anti-CD20-based therapy of B cell lymphoma: state of the art. Leukemia 2002; 16: 2004–2015.

    Article  CAS  PubMed  Google Scholar 

  59. Foran JM, Norton AJ, Micallef IN, Taussig DC, Amess JA, Rohatiner AZ et al. Loss of CD20 expression following treatment with rituximab (chimaeric monoclonal anti-CD20): a retrospective cohort analysis. Br J Haematol 2001; 114: 881–883.

    Article  CAS  PubMed  Google Scholar 

  60. Boye J, Elter T, Engert A . An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003; 14: 520–535.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Mrs Céline Pangault for her technical help in the lymphoma phenotyping. This work was supported in part by the Association pour la Recherche sur le Cancer and the Fondation de France. TP was supported by grants from the Association pour la Recherche sur le Cancer and the Fondation pour la Recherche Médicale. GB was supported by grants from the Fondation de France and the INSERM.

Author information

Author notes

  1. G Barbieri

    Present address: Istituto di Biomedicina ed Immunologia Molecolare, CNR, Palermo, Italy

Authors and Affiliations

  1. INSERM U396, Centre de Recherches Biomédicales des Cordeliers, Paris, France

    T Prod'homme, C De Ruyffelaere, G Barbieri, D Charron & C Alcaide-Loridan

  2. CHU, Service d'Hématologie-Immunologie, Rennes, France

    B Drénou

  3. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland

    W Wiszniewski

  4. Laboratoire de Génétique Oncologique, Centre Henri-Becquerel, Rouen, France

    C Bastard

Authors
  1. T Prod'homme
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Drénou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C De Ruyffelaere
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Barbieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Wiszniewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Bastard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Charron
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Alcaide-Loridan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Alcaide-Loridan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prod'homme, T., Drénou, B., De Ruyffelaere, C. et al. Defective class II transactivator expression in a B lymphoma cell line. Leukemia 18, 832–840 (2004). https://doi.org/10.1038/sj.leu.2403315

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403315

Keywords

This article is cited by

Search

Advanced search

Quick links