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Controlling the Ir Genes
Jeremy M. Boss
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This article cites 17 articles, 10 of which you can access for free at:
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Copyright © 2007 by The American Association of
Immunologists All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
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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
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defined by complementation analysis. Proc. Natl. Acad. Sci. USA 88: 4285– 4288.
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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.
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