Disease relevance of Ciita

• Inhibition of IFN-gamma-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion [1].
• DNA alkylating agents alleviate silencing of class II transactivator gene expression in L1210 lymphoma cells [2].
• The role of the MHC class II transactivator in class II expression and antigen presentation by astrocytes and in susceptibility to central nervous system autoimmune disease [3].
• Furthermore, we demonstrate that the infection of macrophages with M. bovis BCG results in a down-regulation of CIITA mRNA expression and, consequently, in the inhibition of Ia induction [4].
• Here we show that at 5 MOI (multiplicity of infection), recombinant adenoviruses with CIITA or IFN-gamma genes converted virtually all MC-38 colon adenocarcinoma cells and Renca renal carcinoma cells in culture to MHC Class II+/Ii+ cells [5].

High impact information on Ciita

• Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation [6].
• Thus, in addition to its role in transactivation of genes involved in antigen presentation, CIITA plays a critical role during the T cell differentiation by negatively regulating the IL-4 gene transcription [7].
• This transcriptional control is observed in T cells differentiating to the Th1 but not Th2 lineage, consistent with induction of expression of the CIITA gene in T cells by IFNgamma [7].
• A novel role for the major histocompatibility complex class II transactivator CIITA in the repression of IL-4 production [7].
• Class II transactivator (CIITA) is known as a coactivator for MHC class II gene expression in antigen-presenting cells [7].

Chemical compound and disease context of Ciita

• Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette-Guérin involves class II transactivator and depends on the Nramp1 gene [4].
• In the dextran sodium sulfate-induced acute colitis, a disease involving innate immunity, CIITA transgenic mice and wild type control mice showed similar progression of the disease [8].

Biological context of Ciita

• The RAG mutation might therefore reside in the C2ta transcript nuclear export or translation, or in the stability of the CIITA protein [9].
• Interleukin-4 biases differentiation of B cells from Trypanosoma cruzi-infected mice and restrains their fratricide: role of Fas ligand down-regulation and MHC class II-transactivator up-regulation [10].
• The inability of trophoblasts to express MHC class II genes is primarily due to lack of the class II transactivator (CIITA), a transacting factor that is required for constitutive and IFN-gamma-inducible MHC class II transcription [11].
• Histone acetylation regulates the cell type specific CIITA promoters, MHC class II expression and antigen presentation in tumor cells [12].
• Class II transactivator-mediated regulation of major histocompatibility complex class II antigen expression is important for hematopoietic progenitor cell suppression by chemokines and iron-binding proteins [13].

Anatomical context of Ciita

• In contrast, in the RAG cell line, C2ta transcripts were expressed at normal levels, from the proper initiation site [9].
• These data evidence a new type of defect in a MHC class II-defective tumor cell line, as we show here that the alteration in the RAG cells occurs downstream of C2ta transcription [9].
• In these knockout mice, MHC class II expression is nearly eliminated, although a faint RT-PCR signal is visible in spleen, lymph node, and thymus, suggestive of the presence of CIITA-independent regulation of MHC class II expression [14].
• These results show that MHC-II-restricted Ag presentation, and its indirect influences on T cells, remains the only pathway under direct control by CIITA in vivo [15].
• It has recently been suggested that CIITA also regulates numerous other genes having diverse functions within and outside the immune system [15].

Associations of Ciita with chemical compounds

• Reduced IL-4-, lipopolysaccharide-, and IFN-gamma-induced MHC class II expression in mice lacking class II transactivator due to targeted deletion of the GTP-binding domain [14].
• TSA induction of PI-CIITA was restricted to macrophage and dendritic cell lines [12].
• In addition, MHC class II-bearing macrophages were observed in cuprizone-induced inflammatory and demyelinating brain lesions of CIITA KO mice [16].
• Gentamicin injury also induced both CIITA and class II expression, independent of IFN-gamma, in WT and GKO mice [17].
• The removal of the leucine rich region in CIITA blocks activation of MHC II without altering repression of collagen transcription [18].

Physical interactions of Ciita

• An N-terminal 36 amino acids of CIITA mediates suppression of the collagen alpha(2)(I) promoter via binding to CREB-binding protein (CBP) [19].
• Hyper-phosphorylated CIITA interacts with co-activator p300, RFX5 and CIITA itself, which in turn results in induction of MHC class II promoter activity [20].

Regulatory relationships of Ciita

• In all, these data suggest that CIITA negatively regulates expression of IL-10, and that CIITA may direct DC function in ways that extend beyond control of MHC class II [21].
• ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages [22].
• Cutting edge: the class II transactivator prevents activation-induced cell death by inhibiting Fas ligand gene expression [23].
• Therefore, CIITA plays a key role to repress Th2-type cytokine expression as naive CD4 T cells differentiate toward the Th1 lineage [24].
• RESULTS: Elimination of CIITA greatly enhanced graft survival (median survival time [MST] 36 days) over the survival of wild-type (MST 9 days) and even over Abeta (MST 20 days) cardiac grafts [25].

Other interactions of Ciita

• Cathepsin E: a novel target for regulation by class II transactivator [26].
• Expression of class II transactivator (CIITA), the transcriptional regulator that controls all class II expression, is controlled in cell lines in vitro by three promoters: the dendritic cell promoter PI, the B cell promoter PIII, and the interferon-gamma (IFN-gamma)-inducible promoter, PIV [27].
• METHODS: Donor islets from NOD mice deficient in one or both of beta2-microglobulin and class II transactivator genes were transplanted into diabetic NOD mice [28].
• Further evidence of CIITA-independent class II expression elicited by TSA was obtained using knockout mice with defects in CIITA, STAT-1alpha and IRF-1 expression [12].
• 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 [19].

Analytical, diagnostic and therapeutic context of Ciita

• Cornea allografts from wild-type and CIITA KO mice suffered similar rejection fates, whereas far fewer class II-deficient corneas were rejected [16].
• Most importantly, truncated CIITA occupied the collagen alpha 2(I) gene (col1a2) transcription start site during IFN-gamma treatment, but it did not occupy the MHC II promoter as judged by chromatin immunoprecipitation assays [18].
• To understand the role of CIITA in vivo, we have used gene targeting to generate mice that lack CIITA [29].
• Here we show that ovariectomy up-regulates IFN-gamma-induced class II transactivator, a multitarget immune modulator, resulting in increased antigen presentation by macrophages, enhanced T cell activation, and prolonged lifespan of active T cells [30].
• Adoptive transfer studies show that the paucity of CD4 T cells in NOD-CIITA knockout mice is responsible for the absence of diabetes, since the CD8 T cell and B cell compartments are functional [31].

References