Major histocompatibility complex class II (MHCII) molecules drive the development, activation and homeostasis of CD4* T-helper cells. They play a central role in key processes of the adaptive immune system, such as the generation of T-cell-mediated immune responses, the regulation of antibody production and the development and maintenance of tol erance. It is thus not surprising that the absence of MHCII expression results in a severe primary immunodeficiency disease (the bare lymphocyte syndrome (BLS)). The genetic defects responsible for BLS do not lie within the MHCII locus, but in genes encoding transcription factors required for MHCII expression. A great deal of our current knowledge about the mechanisms regulating expression of MHCII genes has been derived from the study of BLS. Four different MHCII regulatory genes have been identified. These genes encode RFXANK, RFXS, RFXAP and CIITA. The first three are subunits of RFX, a ubiquitously expressed factor that binds to the promoters of all MHCII genes. RFX binds co-operatively with other factors to form a highly stable multiprotein complex referred to as the MHCII enhanceosome. This enhanceosome serves as a landing pad for the co-activator CIITA, which is recruited via protein-protein interactions CIITA is the master control factor for MHCII expression. The highly regulated expression pattern of CIITA ultimately dictates the cell type specificity, induction and level of MHCII expression.

Major histocompatibility complex class II (MHC-II

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Major histocompatibility complex class II (MHCII) molecules play a pivotal role in the immune system because they direct the development and activation of CD4 ؉ T cells. There are three human MHCII isotypes, HLA-DR, HLA-DQ, and HLA-DP. Key transcription factors controlling MHCII genes have been identified by virtue of the fact that they are mutated in a hereditary immunodeficiency resulting from a lack of MHCII expression. RFXAP-one of the factors affected in this disease-is a subunit of RFX, a DNA-binding complex that recognizes the X box present in all MHCII promoters. To facilitate identification of conserved regions in RFXAP, we isolated the mouse gene. We then delimited conserved domains required to restore endogenous MHCII expression in cell lines lacking a functional RFXAP gene. Surprisingly, we found that 80% of RFXAP is dispensable for the reactivation of DR expression. Only a short C-terminal segment of the protein is essential for this isotype. In contrast, optimal expression of DQ and DP requires a larger C-terminal segment. These results define an RFXAP domain with an MHCII isotype-specific function. Expression of the three MHCII isotypes exhibits a differential requirement for this domain. We show that this is due to a differential dependence on this domain for promoter occupation and recruitment of the coactivator CIITA in vivo.Major histocompatibility complex class II (MHCII) molecules are heterodimeric (␣-chain-␤-chain) transmembrane glycoproteins displayed at the surfaces of specialized cells of the immune system. In humans there are three MHCII isotypes-HLA-DR, HLA-DQ, and HLA-DP-encoded by distinct pairs of ␣-and ␤-chain genes (40). MHCII molecules present peptides to the T-cell antigen receptor of CD4 ϩ T cells. The recognition of MHCII-peptide complexes by the T-cell antigen receptor of CD4 ϩ T cells represents an interaction that is of pivotal importance for the adaptive immune system because it controls the development, activation, proliferation, and life span of these cells (6,44). Given these key functions, it is not surprising that MHCII expression is tightly controlled and restricted to specialized cells of the immune system. In general, expression of the three MHCII isotypes is coordinated.Expression of MHCII genes is controlled primarily at the level of their transcription by a well-defined regulatory module that is conserved in the promoter-proximal regions of all MHCII genes (reviewed in references 3, 20, 31, and 39). This MHCII regulatory module consists of four cis-acting sequences referred to as the S, X, X2, and Y boxes. The molecular mechanisms that control the MHCII regulatory module have been elucidated to a large extent by the study of a severe hereditary immunodeficiency disease called MHCII deficiency or the bare lymphocyte syndrome (22, 31, 45). As its name implies, this disease is due to the absence of MHCII expression. The genetic defects that are responsible for the disease lie in genes encoding trans-acting regulatory factors that are essential and highly specific f...

The comparison of the rat H1 zero gene promoter sequence with that of known H1 zero genes showed a high evolutionary conservation of regulatory elements involved in the control of the basal transcription of the gene. This finding suggests that the regulation of H1 zero gene expression is also controlled by a very conserved mechanism within vertebrates. In order to confirm this hypothesis, we destroyed three major cis-acting elements in the H1 zero gene promoter by site-directed mutagenesis and showed that these mutations affect significantly the activity of this promoter in cell lines representative of different vertebrate classes (fishes, amphibians, reptiles, birds, and mammals). We concluded that H1 zero gene activity, which is a developmentally regulated process, has been under a great selective pressure during evolution to ensure the expression of the protein at crucial periods of vertebrate development. One of these elements, the H4 box, helps to define within vertebrate H1 genes those encoding differentiation-specific subtypes. Indeed, it is only present in the proximal promoter region of H1 zero and H5 encoding genes. Regarding this feature of the vertebrate differentiation-specific H1 genes, they appear closer to the invertebrate (sea urchin) H1 genes than to those encoding vertebrate replication-dependent (RD) H1. This observation suggests that histone H1 zero and H5 are members that diverged from the main group of histone H1 before the vertebrate histone H1 and that the regulation of vertebrate RD H1 genes has probably evolved toward a coordinate regulation with that of core histone genes.