The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Viktor Steimle - One of the best experts on this subject based on the ideXlab platform.
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pml promotes MHC Class II gene expression by stabilizing the Class II transactivator
Journal of Cell Biology, 2012Co-Authors: Tobias Ulbricht, Viktor Steimle, Mohammad Alzrigat, Almut Horch, Nina Reuter, Anna Von Mikecz, Eberhard Schmitt, Oliver H Kramer, Thomas StammingerAbstract:Promyelocytic leukemia (PML) nuclear bodies selectively associate with transcriptionally active genomic regions, including the gene-rich major histocompatibility (MHC) locus. In this paper, we have explored potential links between PML and interferon (IFN)-γ–induced MHC Class II expression. IFN-γ induced a substantial increase in the spatial proximity between PML bodies and the MHC Class II gene cluster in different human cell types. Knockdown experiments show that PML is required for efficient IFN-γ–induced MHC II gene transcription through regulation of the Class II transactivator (CIITA). PML mediates this function through protection of CIITA from proteasomal degradation. We also show that PML isoform II specifically forms a stable complex with CIITA at PML bodies. These observations establish PML as a coregulator of IFN-γ–induced MHC Class II expression.
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cIIta leucine rich repeats control nuclear localization in vivo recruitment to the major histocompatibility complex MHC Class II enhanceosome and MHC Class II gene transactivation
Molecular and Cellular Biology, 2000Co-Authors: Sandra B Hake, Krzysztof Masternak, Claudia Kammerbauer, Christian Janzen, Viktor SteimleAbstract:The major histocompatibility complex (MHC) Class II transactivator CIITA plays a pivotal role in the control of the cellular immune response through the quantitative regulation of MHC Class II expression. We have analyzed a region of CIITA with similarity to leucine-rich repeats (LRRs). CIITA LRR alanine mutations abolish both the transactivation capacity of full-length CIITA and the dominant-negative phenotype of CIITA mutants with N-terminal deletions. We demonstrate direct interaction of CIITA with the MHC Class II promoter binding protein RFX5 and could also detect novel interactions with RFXANK, NF-YB, and -YC. However, none of these interactions is influenced by CIITA LRR mutagenesis. On the other hand, chromatin immunoprecipitation shows that in vivo binding of CIITA to the MHC Class II promoter is dependent on LRR integrity. LRR mutations lead to an impaired nuclear localization of CIITA, indicating that a major function of the CIITA LRRs is in nucleocytoplasmic translocation. There is, however, evidence that the CIITA LRRs are also involved more directly in MHC Class II gene transactivation. CIITA interacts with a novel protein of 33 kDa in a manner sensitive to LRR mutagenesis. CIITA is therefore imported into the nucleus by an LRR-dependent mechanism, where it activates transcription through multiple protein-protein interactions with the MHC Class II promoter binding complex.
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Quantitative control of MHC Class II expression by the transactivator CIITA
European Journal of Immunology, 1998Co-Authors: Luc A. Otten, Viktor Steimle, Séverine Bontron, Bernard MachAbstract:Activation of T lymphocytes is quantitatively controlled by the level of expression of MHC Class II molecules. Both constitutive and inducible expression of MHC Class II genes is regulated by the transactivator CIITA, which is itself tightly regulated. Since the level of MHC Class II molecules expressed is a functionally essential parameter, it was of interest to explore whether MHC Class II expression is quantitatively controlled by the level of the transactivator. This report shows that in a variety of experimental conditions one does indeed observe, in both mouse and man, a quantitative control of MHC Class II expression by the level of CIITA. This relationship between the regulator gene, which behaves as a rate-limiting factor, and its target genes clarifies our understanding of the quantitative modulation of MHC Class II expression, and thus of T lymphocyte activation.
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the two novel MHC Class II transactivators rfx5 and cIIta both control expression of hla dm genes
International Immunology, 1995Co-Authors: Ilse Kern, Viktor Steimle, Claireanne Siegrist, Bernard MachAbstract:MHC-encoded HLA-DMA and -DMB molecules are atypical MHC chains that play an essential role in antigen presentation by MHC Class II molecules. They resemble both MHC Class I and II molecules but are not expressed at the cell surface. From the study of MHC Class II regulatory mutants, it was found recently that two novel transactivators, CIITA and RFX5, are essential for the control of MHC Class II gene expression. We report here that CIITA and RFX5, although operating at different levels of transcriptional control, are also both essential regulators of HLA-DMA and -DMB genes. This is true for both the constitutive and the inducible mode of DM gene expression. Indeed, both CIITA and RFX5 cDNA can correct the HLA-DMA and -DMB gene expression defect in the respective regulatory mutants. The involvement of these two transcription factors accounts for the coordinate expression of MHC Class II and HLA-DM, two sets of molecules that perform quite different functions in the overall process of antigen presentation.
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regulation of MHC Class II expression by interferon gamma mediated by the transactivator gene cIIta
Science, 1994Co-Authors: Viktor Steimle, Claireanne Siegrist, Annick Mottet, B Lisowskagrospierre, Bernard MachAbstract:Major histocompatibility complex (MHC) Class II genes are expressed constitutively in only a few cell types, but they can be induced in the majority of them, in particular by interferon-gamma (IFN-gamma). The MHC Class II transactivator gene CIITA is defective in a form of primary MHC Class II deficiency. Here it is shown that CIITA expression is controlled and induced by IFN-gamma. A functional CIITA gene is necessary for Class II induction, and transfection of CIITA is sufficient to activate expression of MHC Class II genes in Class II-negative cells in the absence of IFN-gamma. CIITA is therefore a general regulator of both inducible and constitutive MHC Class II expression.
Bernard Mach - One of the best experts on this subject based on the ideXlab platform.
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genetic and molecular definition of complementation group d in MHC Class II deficiency
Human Molecular Genetics, 1998Co-Authors: Marie Claude Fondaneche, Jean Villard, Wojciech Wiszniewski, Emmanuelle Jouanguy, Amos Etzioni, Francoise Le Deist, Ad Peijnenburg, Jeanlaurent Casanova, Walter Reith, Bernard MachAbstract:Four complementation groups, A, B, C and D, have been described among cell lines defective in the coordinate expression of MHC Class II genes. These include cell lines established from patients affected with MHC Class II deficiency and experimentally generated mutant cell lines. Group D, in contrast to the other groups, was for a long time represented only by the 6.1.6 mutant cell line. The gene responsible for the defect in this group, RFXAP, recently was cloned and found to be mutated in the 6.1.6 cell line and in three patients. Here we report fusion experiments in several new HLA Class II-deficient patients, completing the Classification of the majority of known patients into the four complementation groups. Patients from five unrelated families were Classified in complementation group D, while nine others fall into complementation groups A and B. None of the patients defined a new complementation group. Full correction of MHC Class II expression was obtained in cells from patients belonging to group D by transfection with the RFXAP cDNA. The RFXAP coding region was found to be mutated in all patients. Mutations were found to be recurrent since only three different mutations have been found in the eight unrelated families reported to date.
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Quantitative control of MHC Class II expression by the transactivator CIITA
European Journal of Immunology, 1998Co-Authors: Luc A. Otten, Viktor Steimle, Séverine Bontron, Bernard MachAbstract:Activation of T lymphocytes is quantitatively controlled by the level of expression of MHC Class II molecules. Both constitutive and inducible expression of MHC Class II genes is regulated by the transactivator CIITA, which is itself tightly regulated. Since the level of MHC Class II molecules expressed is a functionally essential parameter, it was of interest to explore whether MHC Class II expression is quantitatively controlled by the level of the transactivator. This report shows that in a variety of experimental conditions one does indeed observe, in both mouse and man, a quantitative control of MHC Class II expression by the level of CIITA. This relationship between the regulator gene, which behaves as a rate-limiting factor, and its target genes clarifies our understanding of the quantitative modulation of MHC Class II expression, and thus of T lymphocyte activation.
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the two novel MHC Class II transactivators rfx5 and cIIta both control expression of hla dm genes
International Immunology, 1995Co-Authors: Ilse Kern, Viktor Steimle, Claireanne Siegrist, Bernard MachAbstract:MHC-encoded HLA-DMA and -DMB molecules are atypical MHC chains that play an essential role in antigen presentation by MHC Class II molecules. They resemble both MHC Class I and II molecules but are not expressed at the cell surface. From the study of MHC Class II regulatory mutants, it was found recently that two novel transactivators, CIITA and RFX5, are essential for the control of MHC Class II gene expression. We report here that CIITA and RFX5, although operating at different levels of transcriptional control, are also both essential regulators of HLA-DMA and -DMB genes. This is true for both the constitutive and the inducible mode of DM gene expression. Indeed, both CIITA and RFX5 cDNA can correct the HLA-DMA and -DMB gene expression defect in the respective regulatory mutants. The involvement of these two transcription factors accounts for the coordinate expression of MHC Class II and HLA-DM, two sets of molecules that perform quite different functions in the overall process of antigen presentation.
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regulation of MHC Class II expression by interferon gamma mediated by the transactivator gene cIIta
Science, 1994Co-Authors: Viktor Steimle, Claireanne Siegrist, Annick Mottet, B Lisowskagrospierre, Bernard MachAbstract:Major histocompatibility complex (MHC) Class II genes are expressed constitutively in only a few cell types, but they can be induced in the majority of them, in particular by interferon-gamma (IFN-gamma). The MHC Class II transactivator gene CIITA is defective in a form of primary MHC Class II deficiency. Here it is shown that CIITA expression is controlled and induced by IFN-gamma. A functional CIITA gene is necessary for Class II induction, and transfection of CIITA is sufficient to activate expression of MHC Class II genes in Class II-negative cells in the absence of IFN-gamma. CIITA is therefore a general regulator of both inducible and constitutive MHC Class II expression.
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complementation cloning of an MHC Class II transactivator mutated in hereditary MHC Class II deficiency or bare lymphocyte syndrome
Cell, 1993Co-Authors: Viktor Steimle, Luc A. Otten, Madeleine Zufferey, Bernard MachAbstract:Hereditary major histocompatibility complex (MHC) Class II deficiency (or bare lymphocyte syndrome) is a form of severe primary immunodeficiency with a total lack of MHC Class II expression. It is due to a defect in the regulation of MHC Class II genes. A novel gene was isolated by complementation cloning, using an MHC Class II-negative mutant cell line. This gene (CIITA) functions as a transactivator of MHC Class II gene expression and restores expression of all MHC Class II isotypes in mutant cells. In addition, CIITA fully corrects the MHC Class II regulatory defect of cells from patients with bare lymphocyte syndrome. In this disease we have identified a splicing mutation that results in a 24 amino acid deletion in CIITA, resulting in loss of function of the transactivator. Hence, the CIITA gene is essential for MHC Class II gene expression and has been shown to be responsible for hereditary MHC Class II deficiency.
Frank Kontgen - One of the best experts on this subject based on the ideXlab platform.
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targeted disruption of the MHC Class II aa gene in c57bl 6 mice
International Immunology, 1993Co-Authors: Frank Kontgen, Gabriele Suss, Colin L Stewart, Michael Steinmetz, Horst BluethmannAbstract:The MHC Class II gene Aa was disrupted by targeted mutation in embryonic stem (ES) cells derived from C57BL/6 mice to prevent expression of MHC Class II molecules. Contrary to previous reports, the effect of the null-mutation on T cell development was investigated in C57BL/6 mice, which provide a defined genetic background. The complete lack of cell surface expression of MHC Class II molecules in B6-Aa0/Aa0 homozygous mutant mice was directly demonstrated by cytofluorometric analysis using anti-Ab and anti-Ia specific mAbs. Development of CD4+CD8- T cells in the thymus was largely absent except for a small population of thymocytes expressing high levels of CD4 together with low amounts of CD8. The majority of these cells express the TCR at high density. Although mature CD4+CD8- T cells were undetectable in the thymus, some T cells with a CD4+CD8-TCRhigh phenotype were found in lymph nodes and spleen. Peripheral T cells from the mutant mice can be polyclonally activated in vitro with the mitogen concanavalin A. However, they could not be stimulated with staphylococcal enterotoxin B in autologous lymphocyte reactions, thereby demonstrating the absence of MHC Class II expression in these mice. Peripheral B cells in B6-Aa0/Aa0 mutants were functional and responded to the T cell independent antigen levan by the production of antigen-specific IgM antibodies similar to wild-type cells. The B6-Aa0/Aa0 mutant mice described in this study represent an important tool to investigate the involvement of MHC Class II molecules in lymphocyte maturation and the immune response.
Hidde L Ploegh - One of the best experts on this subject based on the ideXlab platform.
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mice deficient in invariant chain and MHC Class II exhibit a normal mature b2 cell compartment
European Journal of Immunology, 2004Co-Authors: Rene Maehr, Manfred Kraus, Hidde L PloeghAbstract:The role of the invariant chain (II), an MHC Class II-associated chaperone, in B cell development is controversial. II deficient mice (II–/– mice) show a defect in B cell development.This defect has been attributed to the absence of a fragment liberated from the II by intramembranous proteolysis. It was proposed that this fragment is required for activation of the NF-κB pathway as a means of controlling B cell maturation. The opposing view holds that defects in the assembly of MHC Class II molecules result in impaired B cell development. Here we demonstrate that a lack of II indeed causes defects in B cell development, with fewer mature B cells in the periphery as previously reported, but that in a compound-mutant from which both II and all MHC Class II subunits are absent, B cell development is normal. We suggest that neither II itself, nor the MHC Class II products are required for normal B cell development.
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t cell engagement of dendritic cells rapidly rearranges MHC Class II transport
Nature, 2002Co-Authors: Marianne Boes, Jan Cerny, Ramiro Massol, Marjolein Op Den Brouw, Tom Kirchhausen, Jianzhu Chen, Hidde L PloeghAbstract:Assembly of major histocompatibility complex (MHC) molecules, which present antigen in the form of short peptides to T lymphocytes, occurs in the endoplasmic reticulum; once assembled, these molecules travel from the endoplasmic reticulum to their final destination. MHC Class II molecules follow a route that takes them by means of the endocytic pathway, where they acquire peptide, to the cell surface. The transport of MHC Class II molecules in 'professional' antigen-presenting cells (APCs) is subject to tight control and responds to inflammatory stimuli such as lipopolysaccharide. To study Class II transport in live APCs, we replaced the mouse MHC Class II gene with a version that codes for a Class II molecule tagged with enhanced green fluorescent protein (EGFP). The resulting mice are immunologically indistinguishable from wild type. In bone-marrow-derived dendritic cells, we observed Class II molecules in late endocytic structures with transport patterns similar to those in Langerhans cells observed in situ. We show that tubular endosomes extend intracellularly and polarize towards the interacting T cell, but only when antigen-laden dendritic cells encounter T cells of the appropriate specificity. We propose that such tubulation serves to facilitate the ensuing T-cell response.
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cathepsin s required for normal MHC Class II peptide loading and germinal center development
Immunity, 1999Co-Authors: Guo-ping Shi, Hidde L Ploegh, Jose A. Villadangos, Richard J. Riese, Glenn Dranoff, Clayton Small, Kathleen J Haley, Harold A. ChapmanAbstract:Major histocompatibility complex (MHC) Class II molecules acquire antigenic peptides after degradation of the invariant chain (II), an MHC Class II-associated protein that otherwise blocks peptide binding. Antigen-presenting cells of mice that lack the protease cathepsin S fail to process II beyond a 10 kDa fragment, resulting in delayed peptide loading and accumulation of cell surface MHC Class II/10 kDa II complexes. Although cathepsin S-deficient mice have normal numbers of B and T cells and normal IgE responses, they show markedly impaired antibody Class switching to IgG2a and IgG3. These results indicate cathepsin S is a major II-processing enzyme in splenocytes and dendritic cells. Its role in humoral immunity critically depends on how antigens access the immune system.
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isolation and characterization of the intracellular MHC Class II compartment
Nature, 1994Co-Authors: Abraham Tulp, Hidde L Ploegh, Bernhard Dobberstein, Desiree Verwoerd, Jean PietersAbstract:An intracellular compartment has been isolated to which MHC Class II molecules are transported on their way to the plasma membrane. They arrive with an associated invariant chain which is then proteolytically processed while MHC Class II molecules acquire antigenic peptide. These loaded Class II molecules then leave the compartment devoid of invariant chain and bound for the plasma membrane. This compartment represents a new stage in the endocytic/ lysosomal pathway.
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mice lacking the MHC Class II associated invariant chain
Cell, 1993Co-Authors: Marianne Lemeur, Stephane Viville, Vincent Lotteau, Andree Dierich, Jacques Neefjes, Hidde L Ploegh, Christophe BenoistAbstract:Abstract The invariant chain (II) has aroused much interest because of its close association with major histocompatibility complex (MHC) Class II molecules. Various functions have been proposed for it; several of these have received experimental support, but most have not been definitively proven, owing largely to uncertainties inherent in the experimental systems employed. We have now generated a line of mice devoid of the invariant chain by introducing a drastic mutation into the II gene. Cells from mutant animals show aberrant transport of MHC Class II molecules, resulting in reduced levels of Class II complexes at the surface, and these do not have the typical compact conformation indicative of tight peptide binding. Consequently, mutant cells present protein antigens very poorly and mutant mice are deficient in producing and at negatively selecting CD4 + T cells.
Alexander Y Rudensky - One of the best experts on this subject based on the ideXlab platform.
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cathepsin s controls MHC Class II mediated antigen presentation by epithelial cells in vivo
Journal of Immunology, 2005Co-Authors: Courtney Beers, Monique J Kleijmeer, Andrew Burich, Janice Griffith, Phillip Wong, Alexander Y RudenskyAbstract:Epithelial cells at environmental interfaces provide protection from potentially harmful agents, including pathogens. In addition to serving as a physical barrier and producing soluble mediators of immunity, such as cytokines or antimicrobial peptides, these cells are thought to function as nonprofessional APCs. In this regard, intestinal epithelial cells are particularly prominent because they express MHC Class II molecules at the site of massive antigenic exposure. However, unlike bone marrow-derived professional APC, such as dendritic cells or B cells, little is known about the mechanisms of MHC Class II presentation by the nonprofessional APC in vivo. The former use the lysosomal cysteine protease cathepsin S (Cat S), whereas thymic cortical epithelial cells use cathepsin L (Cat L) for invariant chain degradation and MHC Class II maturation. Unexpectedly, we found that murine Cat S plays a critical role in invariant chain degradation in intestinal epithelial cells. Furthermore, we report that nonprofessional APC present a Class II-bound endogenous peptide to naive CD4 T cells in vivo in a Cat S-dependent fashion. These results suggest that in vivo, both professional and nonprofessional MHC Class II-expressing APC use Cat S, but not Cat L, for MHC Class II-mediated Ag presentation.
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a role for cathepsin l and cathepsin s in peptide generation for MHC Class II presentation
Journal of Immunology, 2002Co-Authors: Chyisong Hsieh, Courtney Beers, Paul Deroos, Karen Honey, Alexander Y RudenskyAbstract:The enzymes that degrade proteins to peptides for presentation on MHC Class II molecules are poorly understood. The cysteinal lysosomal proteases, cathepsin L (CL) and cathepsin S (CS), have been shown to process invariant chain, thereby facilitating MHC Class II maturation. However, their role in Ag processing is not established. To examine this issue, we generated embryonic fibroblast lines that express CL, CS, or neither. Expression of CL or CS mediates efficient degradation of invariant chain as expected. Ag presentation was evaluated using T cell hybridoma assays as well as mass spectroscopic analysis of peptides eluted from MHC Class II molecules. Interestingly, we found that the majority of peptides are presented regardless of CL or CS expression, although these proteases often alter the relative levels of the peptides. However, for a subset of Ags, epitope generation is critically regulated by CL or CS. This result suggests that these cysteinal proteases participate in Ag processing and generate qualitative and quantitative differences in the peptide repertoires displayed by MHC Class II molecules.
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sequence analysis of peptides bound to MHC Class II molecules
Nature, 1991Co-Authors: Alexander Y Rudensky, Sooncheol Hong, Paula Prestonhurlburt, Avlin K Barlow, Charles A JanewayAbstract:CD4 T cells recognize peptide fragments of foreign proteins bound to self Class II molecules of the major histocompatibility complex (MHC). Naturally processed peptide fragments bound to MHC Class II molecules are peptides of 13-17 amino acids which appear to be precessively truncated from the carboxy terminus, perhaps after binding to the MHC Class II molecule. The finding of predominant self peptides has interesting implications for antigen processing and self-non-self discrimination.