REGULATION OF MHC CLASS-II GENES - LESSONS FROM A DISEASE

Precise regulation of major histocompatibility complex class II (MHC-I I) gene expression plays a crucial role in the control of the immune r esponse. A major breakthrough in the elucidation of the molecular mech anisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cl oning approach has led to the isolation of CIITA and RFX5, two essenti al MHC-II gene transactivators. CIITA and RFX5 are mutated in these pa tients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regul ate MHC-II genes. CIITA was found to be a non-DNA binding transactivat or that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the bindin g of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonst rated that MHC-II promoter activity is dependent on the binding of hig her-order complexes that are formed by highly specific cooperative bin ding interactions between certain MHC-II promoter-binding proteins. Tw o of these proteins belong to families of which the other members, alt hough capable of binding to the same DNA motifs, are probably not dire ctly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulat ion via transcriptional intervention.