Alternative titles; symbols
HGNC Approved Gene Symbol: CIITA
Cytogenetic location: 16p13.13 Genomic coordinates (GRCh38): 16:10,866,206-10,943,021 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.13 | {Rheumatoid arthritis, susceptibility to} | 180300 | 3 | |
| Bare lymphocyte syndrome, type II, complementation group A | 209920 | Autosomal recessive | 3 |
Major histocompatibility complex (MHC) class II determinants (see HLA-DRA, 142860) are cell surface glycoproteins that play an important role in the adaptive immune response by presenting peptide antigens to CD4 (186940)-positive T cells. MCH2TA, or CIITA, is the master regulator of MCH class II gene transcription and contributes to the transcription of MHC class I genes (see HLA-A, 142800) (summary by Al-Kandari et al., 2007).
Hereditary MHC class II deficiency, or bare lymphocyte syndrome type II (209920), occurs in several complementation groups. Steimle et al. (1993) isolated a transactivator of MHC class II gene expression using an MHC class II-negative mutant cell line for complementation cloning. The gene, which they called CIITA for 'class II transactivator,' restored expression of all MHC class II isotypes in mutant cells and fully corrected the MHC class II regulatory defect of cells from patients with bare lymphocyte syndrome.
In a review, Mach et al. (1994) stated that C2TA cDNA codes for a protein of 1,130 amino acids.
Harton and Ting (2000) reviewed the structure of CIITA. CIITA expression is regulated by up to 4 promoters, with constitutive expression generally resulting from promoters I and III in dendritic and B lymphocytes, respectively. Promoter IV is responsible for IFNG-inducible expression in monocytes/macrophages. CIITA has a complex protein domain structure with an N-terminal acidic domain, followed by a pro-ser-thr (PST) domain, a GTP-binding site, a nuclear localization signal domain, and C-terminal leucine-rich regions.
According to Reith (1997), the C2TA gene has been assigned to chromosome 16.
Gross (2021) mapped the CIITA gene to chromosome 16p13.13 based on an alignment of the CIITA sequence (GenBank AF410154) with the genomic sequence (GRCh38).
In a review, Mach et al. (1994) stated that no evidence for direct binding of C2TA to the MHC class II promoter had been found, suggesting that it is not a DNA-binding protein. C2TA mRNA is differentially expressed and can be detected only in HLA class II-positive cell lines and tissues. This tight correlation suggests that expression of HLA class II genes is to a large extent, if not entirely, under the control of C2TA. Mach et al. (1994) referred to experimental results indicating that the C2TA gene is induced by interferon-gamma (IFNG; 147570) and that C2TA is an essential mediator of inducible MHC class II gene expression.
CIITA is a positive regulator of class II major histocompatibility complex gene transcription that is defective in 1 of the 5 complementation groups of class II MHC-negative cell lines. Its N-terminal region is capable of activating transcription from a reporter gene when fused to a DNA binding domain. Mahanta et al. (1997) found that transactivation by CIITA was extremely sensitive to a mutation in TATA box-binding protein (TBP; 600075) that in yeast is known to abolish VP16-mediated transcription but leaves basal transcription unaffected. Overall the mechanism of transactivation by the human B cell-specific CIITA was very similar to that mediated by the herpesvirus transactivator VP16 in the ways that were tested.
Two of the genes defective in the 5 complementation groups identified in class II-negative bare lymphocyte syndrome or in corresponding laboratory mutants have been cloned (Mach et al., 1996). One gene encodes RFX5 (601863), a member of the RFX family of DNA binding proteins; the other, CIITA, encodes a large protein with a defined acidic transcriptional activation domain. The latter protein does not interact with DNA. Scholl et al. (1997) demonstrated that RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA.
The CIITA protein contains motifs similar to those found in GTP-binding proteins. Harton et al. (1999) demonstrated that CIITA binds GTP, and mutations in these motifs decrease its GTP-binding and transactivation activity. Substitution of these motifs with analogous sequences from Ras (see 190020) restores CIITA function. CIITA exhibits little GTPase activity, yet mutations in CIITA that confer GTPase activity reduce transcriptional activity. GTP binding by CIITA correlates with nuclear import. Thus, Harton et al. (1999) concluded that unlike other GTP-binding proteins, CIITA is involved in transcriptional activation that uses GTP binding to facilitate its own nuclear import.
Harton and Ting (2000) reviewed the role of CIITA as a master regulator of class II MHC genes. They noted that modulation of CIITA expression by pathogens such as cytomegalovirus, mycobacteria, chlamydia, and HIV may serve as a pathway to escape the immune system.
Zhu et al. (2000) showed that CIITA appears to act as a scaffold protein for recognition of conserved class II MHC and related gene promoter boxes W (or S), X, and Y, with strict spatial-helical arrangements of the X and Y promoter elements. The X element binds RFX (RFX5/RFXANK (603200)-RFXB/RFXAP (601861)) and CREB (123810), while the Y element binds NFY/CBF (NFYA (189903), NFYB (189904), and NFYC (605344)). CIITA interacts with all 3 mainly through its N-terminal regions.
Raval et al. (2001) reported that CIITA contains an intrinsic acetyltransferase (AT) activity that maps to a region within the N terminus of CIITA, between amino acids 94 and 132. The AT activity is regulated by the C-terminal GTP-binding domain and is stimulated by GTP. CIITA-mediated transactivation depends on the AT activity. Further, Raval et al. (2001) showed that CIITA activates the promoter of the MHC class II genes in the absence of functional TAFII250 (TAF2A; 313650).
Masternak et al. (2003) pointed out that the promoter-proximal S-Y module can direct cell-type-specific and IFNG-induced expression of transiently expressed transfected genes, but it is not sufficient to reproduce the normal pattern of MHC class II expression in the context of chromatin. There is, in addition, a distal region that also functions as a regulatory element known as the locus control region (LCR), which contains clusters of Dnase I hypersensitive sites in MHC class II-positive cells and is required to express class II genes in a cell-type-specific pattern. Masternak et al. (2003) showed that RFXAP and CIITA bind to the LCR and induce long-range histone acetylation from the promoter to as far as 16 kb upstream, RNA polymerase II recruitment, and the synthesis of extragenic transcripts within the LCR.
Tosi et al. (2006) found that infection of a human B-cell line lacking CIITA expression with human T-cell leukemia virus (HTLV)-2 resulted in viral replication unless cells were also transfected with the N-terminal 321 amino acids of CIITA. Mutation analysis defined a minimal sequence within the CIITA N terminus, residues 64 to 144, that suppressed HTLV-2 replication by inhibiting the viral Tax2 transcription activator. Tosi et al. (2006) showed that Tax2 cooperated with CBP (CREBBP; 600140) and p300 (EP300; 602700), but not with PCAF (602303), to enhance viral transcription, and they noted that CIITA interacts with all 3 of these transcription factors. In addition to CIITA, NFYB (189904) and, to a lesser extent, NFYA (189903) also inhibited Tax2-dependent transactivation of the HTLV-2 promoter. Tosi et al. (2006) concluded that CIITA may inhibit Tax2 function, at least in part, through the NFY complex. They proposed that CIITA has a dual-defensive role against pathogens: it increases viral antigen-presenting function and suppresses HTLV-2 replication in infected cells.
Al-Kandari et al. (2007) found that transfection of human embryonic kidney cells with CIITA and ZXDC (615746) resulted in 12-fold activation of MHC class II expression, as well as class I expression. Silencing of ZXDC diminished HLA-DRA transcription. Yeast 2-hybrid and coimmunoprecipitation analyses confirmed that ZXDC interacted with CIITA. Mammalian 2-hybrid and reporter analyses indicated that the C-terminal 170 amino acids of ZXDC bound to the leucine-rich repeats of CIITA and that full activity of ZXDC required its central zinc fingers. Al-Kandari et al. (2007) concluded that, in conjunction with CIITA, ZXDC is an important regulator of MHC class I and class II transcription.
Using gene silencing and reporter assays, Al-Kandari et al. (2007) showed that ZXDA (300235), like ZXDC, interacted with CIITA and was important in transcriptional activation of MHC class II genes. Coimmunoprecipitation analysis revealed that ZXDC interacted with itself and with ZXDA, and the interactions required their zinc finger domains. Al-Kandari et al. (2007) concluded that association of ZXDA and ZXDC is required for efficient interaction with CIITA in a tripartite complex.
Using a transposon-mediated gene activation screen in human cells, Bruchez et al. (2020) showed that MHC2TA had antiviral activity against Ebola virus. MHC2TA induced resistance by activating expression of the p41 isoform of CD74 (142790), which inhibited viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. The authors also found that CD74 p41 could block endosomal entry of coronaviruses, including SARS-CoV-2.
To identify novel fusion transcripts resulting from translocations, Steidl et al. (2011) investigated 2 Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing and showed a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, Steidl et al. (2011) also demonstrated that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (15%). Furthermore, they found that CTIIA is a promiscuous partner of various in-frame gene fusions, and reported that these gene alterations impact survival in primary mediastinal B-cell lymphoma. As functional consequences of CIITA gene fusions, Steidl et al. (2011) identified downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death-1 (CD274/PDL1, 605402 and CD273/PDL2, 605723). These receptor-ligand interactions have been shown to impact antitumor immune responses in several cancers, whereas decreased MHC class II expression has been linked to reduced tumor cell immunogenicity. Thus, Steidl et al. (2011) concluded that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumor-microenvironment interactions across a spectrum of lymphoid cancers.
In a patient with bare lymphocyte syndrome type II, Steimle et al. (1993) identified a splicing mutation that resulted in a 24-amino acid deletion in C2TA, resulting in loss of function of the transactivator. In RJ2.25 cells, which originated from a Burkitt lymphoma, one C2TA allele was completely deleted, while in the other allele an internal deletion removed over half of the coding region. The splice donor site mutation was identified as a G-to-A transition in the splice donor site 3-prime of a 72-bp exon (600005.0001). Exon skipping due to such a splice site mutation would be expected. Only the deleted C2TA mRNA was expressed and only the mutated allele was detected in the patient, suggesting that the mutation was homozygous. The full complementation of MHC class II deficiency in cell lines from these patients with SCID by transfection of C2TA cDNA raised hopes for gene therapy in this disorder; bone marrow transplantation had had poor success.
Mach et al. (1994) reviewed the topic of MHC class II-deficient combined immunodeficiency. In addition to the splice donor site mutation with exon skipping, homozygosity for deletion of the C2TA gene had been demonstrated in another cell line of complementation group A.
Dziembowska et al. (2002) described 3 novel mutations in the MHC2TA gene in 3 patients with MHC class II deficiency with severe immunodeficiency due to lack of MHC class II. Two patients were found to be compound heterozygotes. In the third patient no mutation was found but the level of CIITA transcript was profoundly decreased. This case was said to represent the first described dysfunction of CIITA due to putative mutations in cis regulatory sequences of the gene.
Antigen presentation to T cells by molecules of the major histocompatibility complex is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, Swanberg et al. (2005) finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. They identified a small interval including the Mhc2ta gene and, using a map over 6 inbred strains combined with gene sequencing and expression analysis, they found 2 conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, they found a -168A-G polymorphism in the type III promoter of the MHC2TA gene (600005.0007) to be associated with increased susceptibility to rheumatoid arthritis (180300) and possibly myocardial infarction, as well as with lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma (IFNG; 147570). Swanberg et al. (2005) concluded that polymorphisms in the rat and human MHC2TA gene result in differential MHC molecular expression and are associated with susceptibility to common complex diseases with inflammatory components.
Using microarray and RNA interference analyses in mice deficient in MHC class II and Ciita, Wong et al. (2003) found that Pxna1 (601055) was expressed in dendritic cells (DCs), but not in other immune cells, and was strongly induced by Ciita, which regulates Plxna1 promoter function. Plxna1 was not required for peptide binding to MHC, indicating that Plxna1 is involved in T cell-DC interactions, but not in antigen processing.
Yau et al. (2016) generated a C2ta congenic mouse strain to investigate the effects of natural polymorphisms of the C2ta promoter on MHC class II expression in antigen-presenting cells. They found that a variant in the type I promoter increased expression of MHC class II on macrophages and dendritic cells in both spleen and peripheral blood. The increased expression resulted in increased antigen presentation to T cells in vitro and increased T-cell activation. However, the altered MHC class II expression did not alter disease development in models of rheumatoid arthritis or multiple sclerosis (see 126200). Yau et al. (2016) concluded that MHC2TA polymorphisms regulate MHC class II expression and T-cell responses but do not have a strong impact on development of autoimmune diseases.
In the cell line from patient BLS-2 with bare lymphocyte syndrome type II (209920), Steimle et al. (1993) found homozygosity for a 72-bp deletion, which represented a single exon preceding a G-to-A transition in the donor splice site at its 3-prime end. Villard et al. (2001) stated that this mutation occurred in intron 13.
Bontron et al. (1997) demonstrated compound heterozygosity for 2 mutations of the C2TA gene in a patient (BCH) with bare lymphocyte syndrome of complementation group A (209920). One allele showed a nonsense point mutation at nucleotide 1256: a G-to-T transversion, replacing the glu381 (GAA) codon with a stop (TAA) codon. A second allele showed a G-to-A transition at position +1 of a splice donor sequence (600005.0003), leading to the skipping of an 84-nucleotide-long exon (nucleotides 3349-3432) and to the loss of 28 amino acids (amino acids 1079-1106) of the protein. In addition, the asp1078 (GAC) codon was replaced by a glu (GAG) codon. Villard et al. (2001) stated that the splice site mutation occurred in intron 18.
For discussion of the splice site mutation in the MHC2TA gene that was found in compound heterozygous state in a patient with bare lymphocyte syndrome of complementation group A (209920) by Bontron et al. (1997), see 600005.0002.
In a patient (SP) with type II bare lymphocyte syndrome (209920), Dziembowska et al. (2002) found a G-to-A transition at position 2178 of the MHC2TA cDNA; the consequence was replacement of a tryptophan codon (TGG) by an amber stop codon (TAG). The other allele was not expressed in this patient.
In a patient (RC) with type II bare lymphocyte syndrome (209920), Dziembowska et al. (2002) found 2 different in-frame deletions of the MHC2TA gene: on the paternal allele, deletion of the 81 bp from nucleotide 3003 to nucleotide 3084; and on the maternal allele, deletion of 3 nucleotides, CATdel3193-5 (600005.0006). The 81-bp deletion corresponded to exon skipping between leu964 and asp991 (27 amino acids). Sequencing of the intron at the 3-prime end of the deleted exon showed that the acceptor site was intact. Attempts to sequence the intron at the 5-prime end of the deleted exon were unsuccessful.
For discussion of the 3-bp deletion in the MHC2TA gene (CATdel3193-5) that was found in compound heterozygous state in a patient with type II bare lymphocyte syndrome (209920) by Dziembowska et al. (2002), see 600005.0005.
Swanberg et al. (2005) demonstrated that a -168A-G polymorphism in the type III promoter of the MHC2TA gene (rs3087456) was associated with increased susceptibility to rheumatoid arthritis (180300), and possibly myocardial infarction and multiple sclerosis, as well as with lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma (147570).
In a study of 128 patients with autoimmune Addison disease (240200) and 406 healthy control subjects from continental Italy, Ghaderi et al. (2006) found that the frequency of allele G of MHC2TA was significantly increased among Addison disease patients (39% alleles), compared with 29% in healthy controls (p = 0.003). Similarly, the frequency of AG+GG genotypes was significantly higher among Addison disease patients than among healthy control subjects, in both a codominant (p = 0.012) and a G-dominant model (p = 0.018). Ghaderi et al. (2006) concluded that their study provided the first demonstration of the association of this polymorphism of the MHC2TA gene with genetic risk for Addison disease that appeared to be independent from the well-known association with the polymorphism of HLA class II genes.
Al-Kandari, W., Jambunathan, S., Navalgund, V., Koneni, R., Freer, M., Parimi, N., Mudhasani, R., Fontes, J. D. ZXDC, a novel zinc finger protein that binds CIITA and activates MHC gene transcription. Molec. Immun. 44: 311-321, 2007. [PubMed: 16600381] [Full Text: https://doi.org/10.1016/j.molimm.2006.02.029]
Al-Kandari, W., Koneni, R., Navalgund, V., Aleksandrova, A., Jambunathan, S., Fontes, J. D. The zinc finger proteins ZXDA and ZXDC form a complex that binds CIITA and regulates MHC II gene transcription. J. Molec. Biol. 369: 1175-1187, 2007. [PubMed: 17493635] [Full Text: https://doi.org/10.1016/j.jmb.2007.04.033]
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Ghaderi, M., Gambelunghe, G., Tortoioli, C., Brozzetti, A., Jatta, K., Gharizadeh, B., De Bellis, A., Giraldi, F. P., Terzolo, M., Betterle, C., Falorni, A., on behalf of the Italian Addison Network. MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency. J. Clin. Endocr. Metab. 91: 4107-4111, 2006. [PubMed: 16849401] [Full Text: https://doi.org/10.1210/jc.2006-0855]
Gross, M. B. Personal Communication. Baltimore, Md. 3/3/2021.
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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. Nat. Acad. Sci. 94: 6324-6329, 1997. [PubMed: 9177216] [Full Text: https://doi.org/10.1073/pnas.94.12.6324]
Masternak, K., Peyraud, N., Krawczyk, M., Barras, E., Reith, W. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nature Immun. 4: 132-137, 2003. [PubMed: 12524537] [Full Text: https://doi.org/10.1038/ni883]
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Reith, W. Personal Communication. Geneva, Switzerland 5/30/1997.
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Steidl, C., Shah, S. P., Woolcock, B. W., Rui, L., Kawahara, M., Farinha, P., Johnson, N. A., Zhao, Y., Telenius, A., Neriah, S. B., McPherson, A., Meissner, B., and 15 others. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471: 377-381, 2011. [PubMed: 21368758] [Full Text: https://doi.org/10.1038/nature09754]
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