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

Abstract

MHC class II molecules are pivotal for the adaptive immune system, because they guide the development and activation of CD4+ T helper cells. Fulfilling these functions requires that the genes encoding MHC class II molecules are transcribed according to a strict cell-type-specific and quantitatively modulated pattern. This complex gene-expression profile is controlled almost exclusively by a single master regulatory factor, which is known as the class II transactivator. As we discuss here, differential activation of the three independent promoters that drive expression of the gene encoding the class II transactivator ultimately determines the exquisitely regulated pattern of MHC class II gene expression.

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…23,[30][31][32][33] At the DNA level, this regulatory unit comprises four sequences (S, X, X2 and Y boxes) (Figure 2), the 'SXY module', which is found at all MHC class II genes and highly conserved across vertebrates.…”

“…This complex set of protein-DNA and protein-protein interactions generates the MHC enhanceosome that is crucial for protecting class II promoters against DNA methylation 42 and recruitment of CIITA. CIITA acts as an inducible coactivator (dubbed the 'master controller') to regulate transcription of MHC class II gene expression at several different levels including chromatin modifications, transcriptional initiation and elongation, in a celltype-specific manner (reviewed in Reith et al 23 and Ting et al 43 ). Although the function of the S box is modified by an unidentified factor, CIITA recruitment is highly dependent on the integrity of the S box and the precise spacing between S and X boxes.…”

Revisiting the specificity of the MHC class II transactivator CIITA in vivo

“…CIITA controls the transcription of all MHC-II genes, as well the genes encoding the invariant chain (Ii) and two nonclassical MHC-II molecules (HLA-DM and HLA-DO in man; H2-M and H2-O in mice), which are accessory molecules involved in the intracellular transport and peptide loading of MHC-II molecules [2][3][4][5]. In most situations, the expression pattern of the gene encoding CIITA (MHC2TA in man; C2ta in mice) dictates the cell type specificity and level of MHC-II expression [2][3][4][5].…”

“…CIITA controls the transcription of all MHC-II genes, as well the genes encoding the invariant chain (Ii) and two nonclassical MHC-II molecules (HLA-DM and HLA-DO in man; H2-M and H2-O in mice), which are accessory molecules involved in the intracellular transport and peptide loading of MHC-II molecules [2][3][4][5]. In most situations, the expression pattern of the gene encoding CIITA (MHC2TA in man; C2ta in mice) dictates the cell type specificity and level of MHC-II expression [2][3][4][5]. Two modes of CIITA and MHC-II expression are recognized, constitutive expression in cells specialized for Ag presentation (B cells, macrophages, DC, thymic epithelial cells) and IFN-c-induced expression in most other cell types [2][3][4][5].…”

“…The class II transactivator CIITA functions as a master control factor for the expression of genes required for MHC class II (MHC-II) mediated Ag presentation [1][2][3][4][5]. This MHC-II-mediated Ag presentation is essential for the development of CD4 + T cells in the thymus and for…”