Lessons from the bare lymphocyte syndrome: molecular mechanisms regulatingMHC class II expression

Major histocompatibility complex class II (MHCII) molecules drive the devel opment, activation and homeostasis of CD4(+) T-helper cells. They play a ce ntral role in key processes of che adaptive immune system, such as the gene ration of T-cell-mediated immune responses, the regulation of antibody prod uction and the development and maintenance of tolerance. It is thus not sur prising that the absence of MHCII expression results in a severe primary im munodeficiency disease (the bare lymphocyte syndrome (BLS)). The genetic de fects responsible for BLS do not lie within the MHCII locus, but in genes e ncoding transcription factors required for MHCII expression. A great deal o f our current knowledge about the mechanisms regulating expression of MHCII genes has been derived from the study of BLS. Four different MHCII regulat ory genes have been identified. These genes encode RFXANK, RFX5, 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 w ith other factors to form a highly stable multiprotein complex referred to as the MHCII enhanceosome. This enhanceosome serves as a landing pad for th e co-activator CIITA, which is recruited via protein-protein interactions. CIITA is the master control factor for MHCII expression. The highly regulat ed expression pattern of CIITA ultimately dictates the cell type specificit y, induction and level of MHCII expression.