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Controlling the Ir Genes Jeremy M. Boss This information is current as of June 18, 2017. Subscription Permissions Email Alerts This article cites 17 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/178/11/6675.full#ref-list-1 Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Downloaded from http://www.jimmunol.org/ by guest on June 18, 2017 References J Immunol 2007; 178:6675-6676; ; doi: 10.4049/jimmunol.178.11.6675 http://www.jimmunol.org/content/178/11/6675 Controlling the Ir Genes Jeremy M. Boss1 1 Address correspondence and reprint requests to Dr. Jeremy M. Boss, Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: [email protected] 2 Abbreviations used in this paper: MHC-II, MHC class II; BLS, bare lymphocyte syndrome. Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 www.jimmunol.org gesting that these patients had deficiencies in RFX subunits. Group A was problematic as all of the binding factors were present, but the genes were still silent. Importantly, whereas a W-X-Y box reporter gene was active in wild-type B cells, it was not active in BLS-A group cells, suggesting that the activity of this sequence was critical to the elusive factor. Steimle et al. (14) took advantage of this information and sought to clone the missing factor by constructing a complementation cDNA library where expression of selection markers would be driven by W-X-Y box sequences. The library was used to complement Accolla’s RJ2.2.5 BLS-group A-like cell line. The complementing gene was named the class II transactivator or CIITA. CIITA expression explained why cells expressed MHC-II genes or not. CIITA was expressed in B cells but silenced in plasma cells (15). It was also found to be the factor induced by IFN-␥ (16). It is now accepted that cells that express CIITA also express MHC-II genes. Thus, CIITA has been called the master regulator of MHC-II expression. Today, we know that CIITA functions as a transcriptional coactivator, linking the X-Y box DNA binding factors to the transcriptional control machinery. CIITA serves as a target for multiple protein complexes, most notably histone-modifying complexes, which are necessary for activation of MHC-II promoters. CIITA is the founding member of a family of proteins thought to be involved in intracellular immune defense termed CATERPILLER, NOD, or NACHT proteins (17). CIITA itself is tightly regulated and is subject to epigenetic control as well. Although the CIITA story itself is far from complete, this month’s Pillars of Immunology article (14) solved the mysteries of MHC-II cell type-specific expression and IFN-␥ control of the Ir genes. References 1. Benacerraf, B., and H. O. McDevitt. 1972. Histocompatibility-linked immune response genes. Science 175: 273–279. 2. McDevitt, H. O., and B. Benacerraf. 1969. Genetic control of specific immune responses. Adv. Immunol. 11: 31–74. 3. Steinmetz, M., and L. Hood. 1983. Genes of the major histocompatibility complex in mouse and man. Science 222: 727–733. 4. Collins, T., A. J. Korman, C. T. Wake, J. M. Boss, D. J. Kappes, W. Fiers, K. A. Ault, M. A. J. Gimbrone, J. L. Strominger, and J. S. Pober. 1984. Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts. Proc. Natl. Acad. Sci. USA 81: 4917– 4921. 5. Gladstone, P., and D. Pious. 1978. Stable variants affecting B cell alloantigens in human lymphoid cells. Nature 271: 459 – 461. 6. Accolla, R. S. 1983. Human B cell variants immunoselected against a single Ia antigen subset have lost expression of several Ia antigen subsets. J. Exp. Med. 157: 1053–1058. 7. Benichou, B., and J. L. Strominger. 1991. 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 88: 4285– 4288. 8. Hume, C. R., and J. S. Lee. 1989. Congenital immunodeficiencies associated with absence of HLA class II antigens on lymphocytes result from distinct mutations in trans-acting factors. Hum. Immunol. 26: 288 –309. 9. Mathis, D. J., C. O. Benoist, V. E. Williams II, M. R. Kanter, and H. O. McDevitt. 1983. The murine E ␣ immune response gene. Cell 32: 745–754. Downloaded from http://www.jimmunol.org/ by guest on June 18, 2017 By 1970, it was clear that the genes located in the MHC were key to controlling the ability to produce Abs in response to an immunogen (1, 2). Termed the immune response genes, the actual identification and sequence determination of these genes in the class II region of the human and murine MHCs occurred in the early and mid-1980s (3). By the mid-1980s, it was found that expression of the MHC class II (MHC-II)2 genes was regulated during the development of B lymphocytes and could be induced in many cell types by IFN-␥ (4). At this time, few mammalian gene or cell type-specific transcription factors were known, and the mechanism(s) by which they functioned to recruit RNA polymerases was based mostly on in vitro system models and ignored the complexities of chromatin. For MHC-II genes, the mechanism(s) of tissue-specific and IFN-␥ regulation was a mystery. This mystery would be solved through the exploitation of novel cell lines that were created through mutagenesis and subsequent selection for the loss of MHC-II surface protein expression (5, 6). The genes deficient in these cell lines functioned in trans, suggesting that the mutant genes were trans-acting factors regulating the MHC-II genes. In addition to these cell lines, bare lymphocyte syndrome (BLS) patients were identified that expressed no MHC-II proteins on their peripheral B cells. Cell lines derived from BLS patients formed four complementation groups (A, B, C, and D), each representing a trans-acting factor responsible for MHC-II gene control (7, 8). Conserved sequence motifs termed X and Y boxes were identified upstream of murine and human MHC-II genes (9). The definition of the conserved region was redefined ultimately to include W/Z, X1, X2, and Y box motifs. Collectively, the W-X-Y module was found upstream of all MHC-II and MHCII-related genes (DO, DM, Ii, etc.). The W-X-Y module was required for IFN-␥ and B cell-specific expression (10, 11). Together with the cell lines in hand and the identification of the cis-regulatory elements, biochemistry and molecular genetics could be combined to identify the transcription factors involved. Although the X1 box binding factor RFX and the Y box binding factor NF-Y were discovered first, these factors by themselves could not explain MHC-II cell type- and tissue-specific expression (12, 13). RFX binding activity was found in all cell types examined but was absent in BLS groups B, C, and D, sug- 6676 10. Boss, J. M., and J. L. Strominger. 1986. Regulation of a transfected human class II major histocompatibility complex gene in human fibroblasts. Proc. Natl. Acad. Sci. USA 83: 9139 –9143. 11. Sloan, J. H., and J. M. Boss. 1988. Conserved upstream sequences of human class II major histocompatibility genes enhance expression of class II genes in wild-type but not mutant B-cell lines. Proc. Natl. Acad. Sci. USA 85: 8186 – 8190. 12. Reith, W., S. Satola, C. Herreo-Sanchez, I. Amaldi, B. Lisowska-Grospierre, C. Griscelli, M. R. Hadam, and B. Mach. 1988. 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. 13. Dorn, A., J. Bollekens, A. Staub, C. Benoist, and D. Mathis. 1987. A multiplicity of CCAAT box-binding proteins. Cell 50: 863– 872. PILLARS OF IMMUNOLOGY 14. Steimle, V., L. A. Otten, M. Zufferey, and B. Mach. 1993. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75: 135–146. 15. Silacci, P., A. Mottet, V. Steimble, W. Reith, and B. Mach. 1994. 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. 16. Steimle, V., C.-A. Siegrist, A. Mottet, B. Lisowska-Grospierre, and B. Mach. 1994. Regulation of MHC class II expression by interferon ␥ mediated by the transactivator gene CIITA. Science 265: 106 –108. 17. Harton, J. A., M. W. Linhoff, J. Zhang, and J. P.-Y. Ting. 2002. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J. Immunol. 169: 4088 – 4093. Downloaded from http://www.jimmunol.org/ by guest on June 18, 2017