Regulation of MHC class II gene expression by the class II transactivator

MHC class II molecules are of central importance to the adaptive immune system. MHC-class-II-mediated peptide presentation is essential for positive and negative selection of CD4+ T cells in the thymus, for homeostasis of the mature CD4+ T-cell population in the periphery, and for the initiation, amplification and regulation of protective immune responses.To fulfil their functions, MHC class II molecules must be expressed according to a precise cell-type-specific and quantitatively modulated pattern. Constitutive expression is largely restricted to thymic epithelial cells and antigen-presenting cells — that is, B cells, macrophages and dendritic cells (DCs) — whereas expression by other cell types requires induction by interferon-γ.The key factor that controls almost all qualitative and quantitative aspects of MHC class II expression is the class II transactivator (CIITA), which is a non-DNA-binding co-activator.Mutations in the CIITA gene cause a severe human immunodeficiency syndrome, which is known as bare lymphocyte syndrome. Gene-knockout mice carrying deletions of the corresponding mouse gene (C2ta) also show most features of the human disease.The highly regulated pattern of expression of the gene encoding CIITA dictates where, when and to what level MHC class II genes are expressed. Transcription of the gene encoding CIITA is controlled by a large regulatory region that contains three independent promoters (pI, pIII and pIV). These have different well-defined functions that have been characterized in vivo by analysis of mice carrying targeted deletions of the C2ta promoters pIII and/or pIV.The promoters pI and pIII share the job of driving CIITA expression in all antigen-presenting cells: pI is a myeloid-cell-specific promoter that is activated in macrophages and conventional DC subsets, whereas pIII is a lymphoid-cell-specific promoter that is essential for driving CIITA expression in B cells, activated human T cells and plasmacytoid DCs.The promoter pIV is essential for driving CIITA expression in thymic epithelial cells (TECs) and in cells of non-haematopoietic origin that are stimulated with interferon-γ. Because MHC class II expression by cortical TECs drives positive selection of CD4+ T cells, pIV is essential for CD4+ T-cell development.Dysregulated activation or repression of the promoters that drive the expression of CIITA is associated with various diseases, including infection with various pathogens, autoimmune and inflammatory diseases, and the development of tumours of various origins.Detailed knowledge of the regulation and dysregulation of CIITA expression has set the stage for the development of novel therapeutic strategies aimed at modulating MHC-class-II-mediated antigen presentation.