Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Oct 1;180(4):1367–1374. doi: 10.1084/jem.180.4.1367

Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes

PMCID: PMC2191681  PMID: 7931070

Abstract

The class II transactivator (CIITA) has been shown to be required for major histocompatibility complex (MHC) class II gene expression in B cells and its deficiency is responsible for a hereditary MHC class II deficiency. Here we show that CIITA is also involved in the inducible expression of class II genes upon interferon gamma (IFN-gamma) treatment. The expression of CIITA is also inducible with IFN-gamma before the induction of MHC class II mRNA. In addition, CIITA mRNA expression does not require new protein synthesis, although new protein synthesis is necessary for the transcription of class II. This suggests that synthesis of new CIITA protein may be essential to induce class II gene expression. We also showed that the JAK1 protein tyrosine kinase activity is required to induce the expression of CIITA upon IFN-gamma stimulation. This finding indicates that CIITA is part of the signaling cascade from the IFN-gamma receptor to the activation of class II genes. In addition, the expression of CIITA is sufficient to activate class II genes in the absence of IFN-gamma stimulation suggesting that CIITA is the major regulatory factor for the inducible expression of class II genes. Together, these data suggest that CIITA is the IFN- inducible cycloheximide sensitive factor previously shown to be required for the induction of MHC class II gene expression.

Full Text

The Full Text of this article is available as a PDF (967.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amaldi I., Reith W., Berte C., Mach B. Induction of HLA class II genes by IFN-gamma is transcriptional and requires a trans-acting protein. J Immunol. 1989 Feb 1;142(3):999–1004. [PubMed] [Google Scholar]
  2. Basta P. V., Sherman P. A., Ting J. P. Detailed delineation of an interferon-gamma-responsive element important in human HLA-DRA gene expression in a glioblastoma multiform line. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8618–8622. doi: 10.1073/pnas.85.22.8618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blanar M. A., Boettger E. C., Flavell R. A. Transcriptional activation of HLA-DR alpha by interferon gamma requires a trans-acting protein. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4672–4676. doi: 10.1073/pnas.85.13.4672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Böttger E. C., Blanar M. A., Flavell R. A. Cycloheximide, an inhibitor of protein synthesis, prevents gamma-interferon-induced expression of class II mRNA in a macrophage cell line. Immunogenetics. 1988;28(4):215–220. doi: 10.1007/BF00345497. [DOI] [PubMed] [Google Scholar]
  5. Decker T., Lew D. J., Mirkovitch J., Darnell J. E., Jr Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor. EMBO J. 1991 Apr;10(4):927–932. doi: 10.1002/j.1460-2075.1991.tb08026.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fu X. Y., Kessler D. S., Veals S. A., Levy D. E., Darnell J. E., Jr ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8555–8559. doi: 10.1073/pnas.87.21.8555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fu X. Y., Schindler C., Improta T., Aebersold R., Darnell J. E., Jr The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7840–7843. doi: 10.1073/pnas.89.16.7840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gansbacher B., Zier K. S. HLA class II mRNA accumulation by activated human T cells following growth in conditioned medium. Clin Exp Immunol. 1989 Jun;76(3):440–445. [PMC free article] [PubMed] [Google Scholar]
  9. Glimcher L. H., Kara C. J. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol. 1992;10:13–49. doi: 10.1146/annurev.iy.10.040192.000305. [DOI] [PubMed] [Google Scholar]
  10. Gutch M. J., Daly C., Reich N. C. Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11411–11415. doi: 10.1073/pnas.89.23.11411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Igarashi K., David M., Finbloom D. S., Larner A. C. In vitro activation of the transcription factor gamma interferon activation factor by gamma interferon: evidence for a tyrosine phosphatase/kinase signaling cascade. Mol Cell Biol. 1993 Mar;13(3):1634–1640. doi: 10.1128/mcb.13.3.1634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kara C. J., Glimcher L. H. Developmental and cytokine-mediated regulation of MHC class II gene promoter occupancy in vivo. J Immunol. 1993 Jun 1;150(11):4934–4942. [PubMed] [Google Scholar]
  13. Kara C. J., Glimcher L. H. In vivo footprinting of MHC class II genes: bare promoters in the bare lymphocyte syndrome. Science. 1991 May 3;252(5006):709–712. doi: 10.1126/science.1902592. [DOI] [PubMed] [Google Scholar]
  14. Kara C. J., Glimcher L. H. Three in vivo promoter phenotypes in MHC class II deficient combined immunodeficiency. Immunogenetics. 1993;37(3):227–230. doi: 10.1007/BF00191890. [DOI] [PubMed] [Google Scholar]
  15. Kessler D. S., Veals S. A., Fu X. Y., Levy D. E. Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator. Genes Dev. 1990 Oct;4(10):1753–1765. doi: 10.1101/gad.4.10.1753. [DOI] [PubMed] [Google Scholar]
  16. Khan K. D., Shuai K., Lindwall G., Maher S. E., Darnell J. E., Jr, Bothwell A. L. Induction of the Ly-6A/E gene by interferon alpha/beta and gamma requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6806–6810. doi: 10.1073/pnas.90.14.6806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Levy D. E., Kessler D. S., Pine R., Reich N., Darnell J. E., Jr Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988 Apr;2(4):383–393. doi: 10.1101/gad.2.4.383. [DOI] [PubMed] [Google Scholar]
  18. Lewis J. A. Induction of an antiviral state by interferon in the absence of elevated levels of 2,5-oligo(A) synthetase and eIF-2 kinase. Virology. 1988 Jan;162(1):118–127. doi: 10.1016/0042-6822(88)90400-x. [DOI] [PubMed] [Google Scholar]
  19. Loh J. E., Chang C. H., Fodor W. L., Flavell R. A. Dissection of the interferon gamma-MHC class II signal transduction pathway reveals that type I and type II interferon systems share common signalling component(s). EMBO J. 1992 Apr;11(4):1351–1363. doi: 10.1002/j.1460-2075.1992.tb05180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Loh J. E., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Flavell R. A. Mutant cell lines unresponsive to alpha/beta and gamma interferon are defective in tyrosine phosphorylation of ISGF-3 alpha components. Mol Cell Biol. 1994 Mar;14(3):2170–2179. doi: 10.1128/mcb.14.3.2170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  22. Oi V. T., Jones P. P., Goding J. W., Herzenberg L. A., Herzenberg L. A. Properties of monoclonal antibodies to mouse Ig allotypes, H-2, and Ia antigens. Curr Top Microbiol Immunol. 1978;81:115–120. doi: 10.1007/978-3-642-67448-8_18. [DOI] [PubMed] [Google Scholar]
  23. Pober J. S., Collins T., Gimbrone M. A., Jr, Cotran R. S., Gitlin J. D., Fiers W., Clayberger C., Krensky A. M., Burakoff S. J., Reiss C. S. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature. 1983 Oct 20;305(5936):726–729. doi: 10.1038/305726a0. [DOI] [PubMed] [Google Scholar]
  24. Ryu K., Koide Y., Yamashita Y., Yoshida T. O. Inhibition of tyrosine phosphorylation prevents IFN-gamma-induced HLA-DR molecule expression. J Immunol. 1993 Feb 15;150(4):1253–1262. [PubMed] [Google Scholar]
  25. Schindler C., Fu X. Y., Improta T., Aebersold R., Darnell J. E., Jr Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836–7839. doi: 10.1073/pnas.89.16.7836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
  27. Shan B., Lewis J. A. Interferon-induced expression of different genes is mediated by distinct regulatory pathways. Virology. 1989 May;170(1):277–281. doi: 10.1016/0042-6822(89)90378-4. [DOI] [PubMed] [Google Scholar]
  28. Shuai K., Schindler C., Prezioso V. R., Darnell J. E., Jr Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science. 1992 Dec 11;258(5089):1808–1812. doi: 10.1126/science.1281555. [DOI] [PubMed] [Google Scholar]
  29. Steimle V., Otten L. A., 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 Oct 8;75(1):135–146. [PubMed] [Google Scholar]
  30. Tsang S. Y., Nakanishi M., Peterlin B. M. B-cell-specific and interferon-gamma-inducible regulation of the HLA-DR alpha gene. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8598–8602. doi: 10.1073/pnas.85.22.8598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  32. Watling D., Guschin D., Müller M., Silvennoinen O., Witthuhn B. A., Quelle F. W., Rogers N. C., Schindler C., Stark G. R., Ihle J. N. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature. 1993 Nov 11;366(6451):166–170. doi: 10.1038/366166a0. [DOI] [PubMed] [Google Scholar]
  33. Widera G., Burkly L. C., Pinkert C. A., Böttger E. C., Cowing C., Palmiter R. D., Brinster R. L., Flavell R. A. Transgenic mice selectively lacking MHC class II (I-E) antigen expression on B cells: an in vivo approach to investigate Ia gene function. Cell. 1987 Oct 23;51(2):175–187. doi: 10.1016/0092-8674(87)90145-0. [DOI] [PubMed] [Google Scholar]
  34. Zier K., Gansbacher B., Ikegaki N., Kennett R., Polakova K. Expression of HLA-DR mRNA in T cells following activation is early and can precede DNA synthesis. Autoimmunity. 1989;5(1-2):59–70. doi: 10.3109/08916938909029143. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES