The Piv-Otal Class II Transactivator Promoter Regulates Major Histocompatibility Complex Class II Expression in the Thymus

Recognition of antigen by CD4 ϩ T cells requires presentation of short peptide fragments in the context of het-erodimeric MHC class II molecules (1, 2). Antigen presentation by MHC class II molecules is pivotal to the induction of adaptive immune responses, peripheral tolerance , and central tolerance, as well as being required for CD4 ϩ T cell survival (1–3). Constitutive expression of MHC class II molecules is restricted to APCs: B cells, den-dritic cells and macrophages; and cortical thymic epithelial cells (cTECs), where MHC class II molecules mediate positive selection of CD4 ϩ T cells (4). The expression of MHC class II on APCs can be further upregulated in response to inflammatory mediators such as IFN-␥ and LPS. These stimuli are also able to induce MHC class II expression on other cell types, e.g., epithelial cells and endothelial cells. However, the precise role of inducible MHC class II expression on non-APCs remains unclear, although it has been implicated in many autoimmune diseases, allograft rejection , and clearance of pathogens from the body (5–7). Regulation of MHC class II expression at the transcrip-tional level is complex, and the class II transactivator (CIITA) is a non–DNA-binding transcriptional activator that plays a key role in this process (8, 9). CIITA was first identified in complementation studies as one of the genes responsible for bare lymphocyte syndrome in humans, a congenital disease in which patients lack both constitutive and inducible expression of MHC class II molecules (10). CIITA is thought to mediate transcriptional activation by interacting with a large number of DNA-binding proteins to form a complex that initiates transcription (8, 9). These proteins include RFX5, RFXANK, CREB, and NF-Y, and they bind specific regions in the MHC class II promoter, known as the W, X, and Y boxes (8, 9). It is believed that CIITA provides the specificity for the expression of MHC class II, as the other transcription factors present in the initiating complex are expressed ubiquitously (8, 9). The role of CIITA in the regulation of MHC class II expression has been further dissected in many in vitro and in vivo studies. Transfection of CIITA into cell lines and primary cells that normally lack MHC class II expression has been shown to be sufficient to induce MHC class II expression , while in CIITA-deficient animals, MHC class II mRNA is barely detectable and cell surface expression is absent on the majority …