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ABSTRACT: Regulation of major histocompatibility complex (MHC) class II antigen expression by cytokines has been suggested to play a major role in the initiation and propagation of immune and autoimmune processes. The analysis of class II gene regulation benefits greatly from the existence of mutants with defects in regulatory factors. We report the establishment of a subclone of the human monocytic cell line U937, termed C119/9, with unusual cytokine regulation of MHC class II expression. In contrast to the parental U937 cell line, only tumor necrosis factor (TNF)-alpha, and not interferon (IFN)-gamma induces the expression of MHC class II antigens on C119/9 cells, and paradoxically, this induction was inhibited almost completely by IFN-gamma. The HLA-DR induction is controlled at the transcriptional level by the first 150 bp of the class II promoter which contains all the class II consensus elements. Both HLA-DR and -DQ mRNA are induced by TNF-alpha treatment, and both are diminished upon co-treatment with TNF-alpha and IFN-gamma. This antagonism between TNF-alpha and IFN-gamma seem to be restricted to MHC class II genes. This subline of U937 cells may be useful in further studies of MHC class II regulation.
European Journal of Immunology 12/1995; 25(11):3202-6. · 5.10 Impact Factor
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ABSTRACT: Constitutive major histocompatibility complex (MHC) class II gene expression is tightly restricted to antigen presenting cells and is under developmental control. Cells of the B cell lineage acquire the capacity to express MHC class II genes early during ontogeny and lose this property during terminal differentiation into plasma cells. Cell fusion experiments have suggested that the extinction of MHC class II expression in plasma cells is due to a dominant repression, but the underlying mechanisms are not understood. CIITA was recently identified as an MHC class II transactivator that is essential for MHC class II expression in B lymphocytes. We show here that inactivation of MHC class II genes in plasmocytes is associated with silencing of the CIITA gene. Moreover, experimentally induced expression of CIITA in plasmocytes leads to reexpression of MHC class II molecules to the same level as that observed on B lymphocytes. We therefore conclude that the loss of MHC class II expression observed upon terminal differentiation of B lymphocytes into plasmocytes results from silencing of the transactivator gene CIITA.
Journal of Experimental Medicine 11/1994; 180(4):1329-36. · 13.85 Impact Factor
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ABSTRACT: The X box of major histocompatibility complex class II promoters is essential for proper expression of class II genes. Here we show that two distinct protein-DNA complexes (A and B), which exhibit similar binding characteristics and identical contact points on the X box, can be formed. This suggests the existence of a family of related X box-binding factors. Complex B (and not complex A) is specifically affected in primary combined immunodeficiency, a congenital defect in class II gene regulation. RFX1, the first X box-binding protein cloned, encodes a functionally relevant factor present in complex A and not in complex B as originally suspected. This report also illustrates the need for caution in correlating specific cloned proteins with nuclear factors identified by DNA-binding assays, particularly when dealing with families of related proteins.
Molecular and Cellular Biology 10/1992; 12(9):4076-83. · 5.53 Impact Factor
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ABSTRACT: The regulation of MHC class II gene expression controls T-cell activation and, hence, the immune response. Among the nuclear factors observed to bind to conserved DNA sequences in human leukocyte antigen (HLA) class II gene promoters, RFX is of special interest: Its binding is defective in congenital HLA class II deficiency, a disease of class II gene regulation. The cloning of an RFX cDNA has allowed us to show by transfection of a plasmid directing the synthesis of antisense RFX RNA that RFX is a class II gene regulatory factor. RFX is a novel 979-amino-acid DNA-binding protein that contains three structurally and functionally separate domains. The 91-amino-acid DNA-binding domain is distinct from other known DNA-binding motifs but may be distantly related to the helix-loop-helix motif. The most striking property of RFX is that it can bind stably to the class II X box as either a monomer or a homodimer and that the domain responsible for dimerization is distant from and functionally independent of the DNA-binding domain. This distinguishes RFX from other known dimeric DNA-binding proteins. It also implies that an RFX homodimer has two potential DNA-binding sites. We therefore speculate that RFX could form a DNA loop by cross-linking the two X-box sequences found far apart upstream of MHC class II genes.
Genes & Development 10/1990; 4(9):1528-40. · 11.66 Impact Factor
