Abstract
Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) gene and the MHC class II molecules are physically and functionally associated within class II-expressing cell types. These genes are generally co-expressed in various cell types and coordinately induced by cytokines such as interferon-gamma (IFN-gamma). Human Ii gene shares a regulatory mechanism with MHC class II genes via the X and Y cis-acting elements. Ii X and Y are required for constitutive expression in B lymphoid cell lines and for induction by IFN-gamma in a glioblastoma cell line. The Servenius element (S) contributes 5-fold transcriptional activity to class II gene HLA-DRA, and an S homologue has been implied in Ii gene regulation. Now we report that along with X and Y, the Ii S box functions in a positive manner to regulate Ii transcription in B cell lines but not in T cell lines. In addition, S,X, and Y are all necessary for induced expression of Ii in an IFN-gamma-regulated glioblastoma cell line and in primary untransformed glial cells. Transcriptional activity of Ii X and Y elements correlates with the presence of in vivo protein/DNA interactions in Ii-expressing cells. Most interestingly, in vivo interactions are induced upon IFN-gamma induction in a time-dependent fashion. Thus, the Ii promoter contains elements that coordinately regulate expression with the MHC class II genes, and these functional sites are contacted in vivo emphasizing their importance in Ii gene transcription.
Highlights
From the $.Department of Microbiology and Immunology and the SLineberger Comprehensive Cancer Center; Universityof North Carolina at Chapel Hill, Chapel Hill,North Carolina 27599-7295
Major histocompatibility complex(MHC) class 11-asso- These mice have antigen presenting cells (APC) with reduced ciated invariant chain (Ii) gene and the MHC class I1 capacity to function in antigen presentation, and they have molecules are physically and functionally associated reduced numbers of CD4+ cells in thethymus
X and Y are bound by protein invivo in expressing cell lines (36, 37) and binding at the X box is upregulated in vivo upon IFN-y induction (37)
Summary
From the $.Department of Microbiology and Immunology and the SLineberger Comprehensive Cancer Center; Universityof North Carolina at Chapel Hill, Chapel Hill,North Carolina 27599-7295. X and Y are bound by protein invivo in expressing cell lines (36, 37) and binding at the X box is upregulated in vivo upon IFN-y induction (37). It is known from cross-competitionexperiments in electrophoretic mobility shift assays that Ii Y box binding proteins are thesame or similar to Y box binding proteins of class I1 genes HLA-DQB and HLADRA This study extends the analysis of functional Ii promoter elements in expressing, nonexpressing, and IFN-y-inducible cell types. This study showsthat all three conserved elements, S,X, and Y, are important for constitutive expression in these cell lines, as well as for IFN-y induction in brain glial cells. The kinetics of promoter loading upon IFN-y induction of Ii are different from that of class I1 gene, HLA-DM
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