CIITA Gene: Master Regulator of MHC Class II Expression
Comprehensive guide to the CIITA gene, its function, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | CIITA |
|---|---|
| Full Name | Class II Major Histocompatibility Complex Transactivator |
| Gene Type | Protein coding |
| Chromosomal Location | 16p13.13 |
| NCBI Gene ID | 4261 ncbi.nlm.nih.gov/gene/4261 |
| Ensembl ID | ENSG00000179583 |
| UniProt ID | P33076 |
| OMIM ID | 600005 |
| HGNC ID | 7067 |
| Aliases | C2TA, CIITA-IV, MHC2TA, NLRA |
Description
The CIITA (Class II Major Histocompatibility Complex Transactivator) gene encodes a protein that acts as the master transcriptional coactivator for MHC class II genes. It is not a DNA-binding protein itself but functions by interacting with the enhanceosome complex on MHC class II promoters. CIITA is constitutively expressed in professional antigen-presenting cells (e.g., dendritic cells, B cells, macrophages) and is inducible by interferon-gamma (IFN-γ) in other cell types. It is essential for both constitutive and inducible expression of MHC class II molecules, which are critical for presenting exogenous antigens to CD4+ T helper cells, thereby initiating and regulating adaptive immune responses. Mutations in CIITA lead to a profound immunodeficiency known as bare lymphocyte syndrome type II (BLS II), characterized by a lack of MHC class II expression and severe susceptibility to infections.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Bare Lymphocyte Syndrome Type II (BLS II) | Loss-of-function mutations in CIITA abolish MHC class II expression on the cell surface of antigen-presenting cells. This prevents the presentation of antigens to CD4+ T cells, leading to a severe combined immunodeficiency (SCID) phenotype. The lack of MHC class II also affects thymic selection, resulting in reduced CD4+ T cell counts. | OMIM #209920; Multiple case reports and functional studies confirm that biallelic mutations in CIITA are a primary cause of BLS II. |
| Increased Susceptibility to Infections | The absence of functional MHC class II molecules due to CIITA mutations leads to a failure to mount effective adaptive immune responses against pathogens. Patients suffer from recurrent and severe bacterial, viral, and fungal infections, particularly of the respiratory and gastrointestinal tracts. | Clinical observations in BLS II patients; Functional studies showing impaired antigen presentation in CIITA-deficient cells. |
| Rheumatoid Arthritis (RA) Susceptibility | Certain single nucleotide polymorphisms (SNPs) in the CIITA gene region have been associated with altered expression levels or function of CIITA, which may influence the threshold for T cell activation and contribute to autoimmune responses. However, the exact mechanism is complex and involves multiple genetic and environmental factors. | Genome-wide association studies (GWAS) have identified CIITA as a susceptibility locus for RA (e.g., PMID: 20453841). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymphoid tissues (e.g., spleen, lymph nodes, tonsil) | High (e.g., >50 nTPM) | High expression in professional antigen-presenting cells. |
| Whole blood | Moderate (e.g., 20-50 nTPM) | Expression in B cells, monocytes, and dendritic cells. |
| Lung | Low to Moderate (e.g., 10-20 nTPM) | Inducible expression in alveolar macrophages and epithelial cells upon IFN-γ stimulation. |
| Liver | Low (e.g., <10 nTPM) | Expression mainly in Kupffer cells (liver macrophages). |
| Brain | Low (e.g., <10 nTPM) | Expression in microglia and potentially inducible in other cell types. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Raji (Burkitt's lymphoma, B cell line) | High (e.g., >100 nTPM) | Constitutive high expression typical of mature B cells. |
| THP-1 (Monocytic leukemia) | Moderate (e.g., 30-60 nTPM) | Expression can be significantly upregulated by IFN-γ treatment. |
| HeLa (Cervical carcinoma) | Low (e.g., <10 nTPM) | Basal expression is low but strongly inducible by IFN-γ. |
| K-562 (Chronic myelogenous leukemia) | Very Low (e.g., <5 nTPM) | Minimal expression; often used as a negative control for MHC II expression. |
| MCF7 (Breast adenocarcinoma) | Low (e.g., <10 nTPM) | Expression is inducible by IFN-γ. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.IVS1+2T>C (splice site) | Splice-site mutation | Rare (found in BLS II patients) | Disrupts splicing of CIITA mRNA, leading to a non-functional protein and loss of MHC class II expression. |
| c.1123C>T (p.Arg375Ter) | Nonsense mutation | Rare (found in BLS II patients) | Introduces a premature stop codon, resulting in a truncated, non-functional CIITA protein. |
| c.1621delC (frameshift) | Frameshift mutation | Rare (found in BLS II patients) | Causes a shift in the reading frame, leading to a truncated and non-functional protein. |
| c.2430+1G>A (splice site) | Splice-site mutation | Rare (found in BLS II patients) | Disrupts the donor splice site of intron 14, leading to aberrant mRNA splicing and loss of function. |
Mutation functional classification
Loss of Function (LOF)
The vast majority of disease-causing CIITA mutations are loss-of-function. These include nonsense, frameshift, and splice-site mutations that result in a truncated or absent protein. This leads to a complete lack of MHC class II expression, causing Bare Lymphocyte Syndrome type II.
Gain of Function (GOF)
No clear gain-of-function mutations have been described for CIITA in the context of human disease. Constitutive overexpression of CIITA has been observed in some cancers, but this is typically due to epigenetic changes or upstream signaling alterations rather than activating mutations in the CIITA gene itself.
Dominant Negative (DN)
While most BLS II cases are autosomal recessive, some rare dominant-negative mutations have been reported. These mutations produce a mutant CIITA protein that can interfere with the function of the wild-type protein, likely by forming non-functional multimers or competing for binding partners. This results in an autosomal dominant form of MHC class II deficiency.
View complete mutation data：
Gene Ontology (GO)
| • transcription coactivator activity | • protein binding |
| • DNA-binding transcription factor binding | • nucleus |
| • cytoplasm | • regulation of DNA-templated transcription |
| • positive regulation of gene expression | • immune response |
| • antigen processing and presentation of exogenous peptide antigen via MHC class II | • response to interferon-gamma |
Pathways
• Antigen processing and presentation (MHC class II pathway)
• Interferon-gamma signaling pathway
• Immune System (Reactome: R-HSA-168256)
• Cytokine Signaling in Immune system (Reactome: R-HSA-1280215)
Protein Summary
The CIITA protein (UniProt P33076) is a 1130 amino acid protein that functions as a master transcriptional coactivator. It contains several key domains: an N-terminal acidic domain (AD) that recruits chromatin remodeling factors and the basal transcription machinery, a proline/serine/threonine-rich (PST) domain, a GTP-binding domain (GBD) that is crucial for its function and self-association, and C-terminal leucine-rich repeats (LRRs) that are involved in protein-protein interactions. CIITA does not bind DNA directly but is recruited to MHC class II promoters through interactions with the enhanceosome complex, which includes RFX (RFX5, RFXAP, RFXANK) and CREB. Once recruited, it activates transcription by promoting histone acetylation and chromatin remodeling. Its expression is tightly regulated by promoter IV, which is responsive to IFN-γ signaling via the JAK/STAT pathway.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CIITA Knockout HEK293 Cell Line | EDJ-KQ2578 | Human | 4261 | Details Get a Quote |
| CIITA Knockout HeLa Cell Line | EDJ-KQ23263 | Human | 4261 | Details Get a Quote |
| CIITA Knockout A-549 Cell Line | EDJ-KQ62361 | Human | 4261 | Details Get a Quote |
| CIITA Knockout HCT 116 Cell Line | EDJ-KQ70831 | Human | 4261 | Details Get a Quote |
| B2M +CIITA Knockout THP-1 Cell Line | EDC90693 | Human | 567+4261 | Details Get a Quote |
