The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Peter Cresswell - One of the best experts on this subject based on the ideXlab platform.
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Interaction of Human Immunodeficiency Virus Type 2 Vpx and Invariant Chain
Journal of Virology, 2000Co-Authors: Heather A. Pancio, Peter Cresswell, Nancy Vander Heyden, Kavitha Kosuri, Lee RatnerAbstract:Vpx is a virion-associated protein of human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency viruses. The yeast two-hybrid system was used to identify Invariant Chain (Ii) as a cellular protein that interacts with HIV-2 Vpx. Vpx-Ii interaction was confirmed in cell-free reactions using bacterially expressed glutathione S-transferase fusion proteins and by coimmunoprecipitation in transfected and infected cells. In chronically infected cells expressing Vpx, Ii levels were markedly decreased, presumably due to enhanced degradation. These findings suggest that Vpx may disrupt major histocompatibility complex class II antigen presentation.
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Trimeric Interactions of the Invariant Chain and Its Association with Major Histocompatibility Complex Class II αβ Dimers
Journal of Biological Chemistry, 1996Co-Authors: John R Newcomb, Cerinda Carboy-newcomb, Peter CresswellAbstract:Abstract The Invariant Chain (I Chain) associates with major histocompatibility complex class II αβ heterodimers upon synthesis, preventing them from binding peptides and unfolded proteins in the endoplasmic reticulum and directing class II transport to post-Golgi endosomal compartments. To assess which regions of the I Chain are involved in binding class II molecules, we have studied proteolytic fragments of the I Chain generated both by natural proteolytic degradation of αβ dimer-Invariant Chain complexes (αβ·I) within human B cells and by in vitro digestion of purified αβ·I complexes with proteinase K. The 18-kDa luminal I Chain fragment generated by proteinase K, called K3, remains associated with αβ dimers and retains the complex (αβ·K3) in a high molecular mass nonameric configuration. The N terminus of the K3 fragment was identified as glycine 110. This indicates that the K3 fragment lies outside of the class II-associated Invariant Chain peptide region (amino acids 81-104) of the I Chain, shown to be important for initial αβ·I assembly. An N-terminal 12-kDa I Chain fragment called p12, generated intracellularly, was also analyzed and was found to remain associated with αβ dimers in a high molecular mass form analogous to the nonameric αβ·I complex. These results demonstrate that at least two class II contact points exist along the length of the I Chain and that different regions of the I Chain can stabilize the αβ·I nonamer. Additional evidence suggests that the O-linked glycan(s) characteristic of the I Chain is added to the short C-terminal region absent from the K3 fragment.
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Invariant Chain cleavage and peptide loading in major histocompatibility complex class ii vesicles
Journal of Experimental Medicine, 1995Co-Authors: Sebastian Amigorena, Peter Cresswell, Paul Webster, James R Drake, J Newcomb, Ira MellmanAbstract:B lymphocytes contain a novel population of endocytic vesicles involved in the transport of newly synthesized major histocompatibility complex (MHC) class II alpha beta Chains and alpha beta peptide complexes to the cell surface. We now present evidence that these class II-enriched vesicles (CIIV) are also likely to be a site for the loading of immunogenic peptides onto MHC molecules. We used the serine protease inhibitor leupeptin to accumulate naturally occurring intermediates in the degradation of alpha beta-Invariant Chain complexes and to slow the intracellular transport of class II molecules. As expected, leupeptin caused an accumulation of Ii Chain and class II molecules (I-A(d)) in endosomes and lysosomes. More importantly, however, it enhanced the selective accumulation of a 10-kD Invariant Chain fragment associated with sodium dodecyl sulfate (SDS)-labile (empty) alpha beta dimers in CIIV. This was followed by the dissociation of the 10-kD fragment, formation of SDS-stable (peptide-loaded) alpha beta dimers, and their subsequent appearance at the cell surface. Thus, CIIV are likely to serve as a specialized site, distinct from endosomes and lysosomes, that hosts the final steps in the dissociation of Invariant Chain from class II molecules and the loading of antigen-derived peptides onto newly synthesized alpha beta dimers.
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transport and intracellular distribution of mhc class ii molecules and associated Invariant Chain in normal and antigen processing mutant cell lines
Journal of Cell Biology, 1994Co-Authors: Janice M Riberdy, R R Avva, H J Geuze, Peter CresswellAbstract:We have compared the intracellular transport and subcellular distribution of MHC class II-Invariant Chain complexes in a wild-type HLA-DR3 homozygous cell line and a mutant cell line, T2.DR3. The latter has a defect in antigen processing and accumulates HLA-DR3 molecules associated with an Invariant Chain-derived peptide (CLIP) rather than the normal complement of peptides derived from endocytosed proteins. We find that in the wild-type cells, CLIP is transiently associated with HLA-DR3 molecules, suggesting that the peptide is a normal class II-associated intermediate generated during proteolysis of the Invariant Chain. In the mutant cell line proteolysis of the Invariant Chain is less efficient, and HLA-DR3/CLIP complexes are generated much more slowly. Examination of the mutant cell line by immunoelectronmicroscopy shows that class II-Invariant Chain complexes accumulate intracellularly in large acidic vesicles which contain lysosomal markers, including beta-hexosaminidase, cathepsin D, and the lysosomal membrane protein CD63. The markers in these vesicles are identical to those seen in the class II-containing vesicles (MIICs) seen in the wild-type cells but the morphology is drastically different. The vesicles in the mutant cells are endocytic, as measured by the internalization of BSA-gold conjugates. The implication of these findings for antigen processing in general and the nature of the mutation in particular are discussed.
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Transport properties of free and MHC class ll-associated oligomers containing different isoforms of human Invariant Chain
International Immunology, 1994Co-Authors: Balasubramanian Arunachalam, Carilee A. Lamb, Peter CresswellAbstract:Major histocompatibility complex (MHC) class II molecules are heterodimers of alpha and beta subunits that associate intracellularly with the Invariant Chain. Human Invariant Chain exists in four forms, p33, p35, p41, and p43, generated by a combination of alternative initiation of translation and alternative splicing. The biological significance of the existence of the different forms of Invariant Chain is still unclear and to date no study has compared all four using one system. We have compared them for their transport characteristics and for their ability to transport associated MHC class II heterodimers into the endocytic pathway. Here we report that hetero oligomers containing p33 and p35 or p41 and p43 remain in the endoplasmic reticulum (ER) in the absence of class II alpha and beta Chains. This is consistent with earlier reports suggesting that the N-terminal extension shared by p35 and p43 contains an ER retention signal. Homo oligomers containing only the p33 or p41 forms of Invariant Chain exit the ER and are sorted to endosomes following passage through the Golgi apparatus. Their accumulation leads to enlargement of the endosomes. Quantitation of the turnover rates of the p35/p33 forms with the alternatively spliced p43/p41 forms indicates that the latter are more stable, both in the ER and following transport through the Golgi apparatus. When class II molecules are co-expressed with p33 and p35, or p41 and p43, the assembled complex is efficiently transported to the endocytic pathway.
Arjan A Van De Loosdrecht - One of the best experts on this subject based on the ideXlab platform.
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class ii associated Invariant Chain peptide as predictive immune marker in minimal residual disease in acute myeloid leukemia
OncoImmunology, 2014Co-Authors: Marvin M Van Luijn, Willemijn Van Den Ancker, Arjan A Van De LoosdrechtAbstract:The majority of patients with acute myeloid leukemia (AML) reach complete remission after high-dose chemotherapy. Still, half of these patients experience a relapse due to presence of minimal residual disease (MRD). Here we discuss the poor prognostic role of class II-associated Invariant Chain peptide (CLIP) expression on residual leukemic cells.
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tumor immune escape in acute myeloid leukemia class ii associated Invariant Chain peptide expression as result of deficient antigen presentation
OncoImmunology, 2012Co-Authors: Marvin M Van Luijn, Martine E D Chamuleau, Gert J Ossenkoppele, Arjan A Van De LoosdrechtAbstract:In this overview, we discuss the role of class II-associated Invariant Chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.
Oddmund Bakke - One of the best experts on this subject based on the ideXlab platform.
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mhc ii and the endocytic pathway regulation by Invariant Chain
Scandinavian Journal of Immunology, 2009Co-Authors: Ole J B Landsverk, Oddmund Bakke, Tone F GregersAbstract:The major histocompatibility complex (MHC) class I and II molecules perform vital functions in innate and adaptive immune responses towards invading pathogens. MHC class I molecules load peptides in the endoplasmatic reticulum (ER) and display them to the T cell receptors (TcR) on CD8+ T lymphocytes. MHC class II molecules (MHC II) acquire their peptides in endosomes and present these to the TcR on CD4+ T lymphocytes. They are vital for the generation of humoral immune responses. MHC II assembly in the ER and trafficking to endosomes is guided by a specialized MHC II chaperone termed the Invariant Chain (Ii). Ii self-associates into a trimer in the ER, this provides a scaffold for the assembly of three MHC II heterodimers and blocks their peptide binding grooves, thereby avoiding premature peptide binding. Ii then transports the nascent MHC II to more or less specialized compartment where they can load peptides derived from internalized pathogens.
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mechanism of interaction between leucine based sorting signals from the Invariant Chain and clathrin associated adaptor protein complexes ap1 and ap2
Journal of Biological Chemistry, 2002Co-Authors: Thomas L Kongsvik, Oddmund Bakke, Stefan Honing, Dmitrii G RodionovAbstract:Abstract The cytoplasmic tail of the Invariant Chain contains two leucine-based sorting signals, and each of those seems sufficient to route the Invariant Chain to its intracellular destination in either normal or polarized cells. It is believed that the intracellular routing of the Invariant Chain is mediated by its interactions with the clathrin-associated adaptor protein complexes AP1 and AP2. We (1) have previously demonstrated the in vitrointeractions between the cytoplasmic tail of the Invariant Chain and AP1/AP2 complexes. These interactions were specific and depended on the critical leucine residues in the Invariant Chain's sorting signals. In the present study, we decided to investigate the molecular mechanism of these interactions. To this end, we constructed a set of glutathioneS-transferase fusion proteins that contained the intact cytoplasmic tail of the Invariant Chain and its various mutants to define residues important for its interactions with AP1 and AP-2. Our results demonstrated the importance of several residues other than the critical leucine residues for such interactions. A strong correlation between in vitro binding of AP2 to the Invariant Chain and in vivo internalization of the Invariant Chain was observed, confirming the primary role of AP2 in recognition of endocytic signals. In addition, we demonstrated different requirements for AP1 and AP2 binding to cytoplasmic tail of the Invariant Chain, which may reflect that the different sorting pathways mediated by AP1 and AP2 involve their recognition of the primary structure of the sorting signal.
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the leucine based sorting motifs in the cytoplasmic domain of the Invariant Chain are recognized by the clathrin adaptors ap1 and ap2 and their medium Chains
Journal of Biological Chemistry, 1999Co-Authors: Michael Hofmann, Stefan Honing, Dmitrii G Rodionov, Bernhard Dobberstein, Kurt Von Figura, Oddmund BakkeAbstract:Abstract Recognition of sorting signals within the cytoplasmic tail of membrane proteins by adaptor protein complexes is a crucial step in membrane protein sorting. The three known adaptor complexes, AP1, AP2, and AP3, have all been shown to recognize tyrosine- and leucine-based sorting signals, which are the most common sorting signals within membrane protein cytoplasmic tails. Although tyrosine-based signals are recognized by the μ-Chains of adaptor complexes, the subunit recognizing leucine-based sorting signals is less clear. In this report we show by surface plasmon resonance that the two leucine-based sorting signals within the cytoplasmic tail of the Invariant Chain bind independently from each other to AP1 and AP2 but not to AP3. We also show that both motifs can be recognized by the μ-Chains of AP1 and AP2. Moreover, by using monomeric as well as trimeric Invariant Chain constructs, we show that adaptor binding does not require trimerization of the Invariant Chain.
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MHC Class II-Associated Invariant Chain-Induced Enlarged Endosomal Structures: A Morphological Study☆
Experimental Cell Research, 1997Co-Authors: Espen Stang, Oddmund BakkeAbstract:Abstract The major histocompatibility complex class II-associated Invariant Chain is believed to direct newly synthesized class II to endocytic compartments. Invariant Chain synthesized at high levels in transiently transfected cells induces formation of large vesicular structures. We have examined the effect of stable expression of Invariant Chain in human fibroblasts by light and electron microscopy. Invariant Chain expression dramatically modified endocytic compartments and induced the formation of greatly enlarged structures. These modifications were not lethal. Ultrastructurally, at least three morphologically distinct enlarged compartments could be discerned in the cells. These three compartments may represent early and late endosomes and lysosomes. Internalization of anti-Invariant Chain antibodies shows that Invariant Chain may reach the large endosomes via rapid internalization from the plasma membrane. Internalized protein remained in the enlarged vesicles for 4–6 h, indicating an Invariant Chain-induced delay in the pathway to lysosomes. Although the large Invariant Chain-induced vesicles have not yet been seen in professional antigen-presenting cells, the Invariant Chain-induced effects may play a role in regulating the endocytic pathway, creating a special environment for MHC class II to bind antigen.
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The various roles of Invariant Chain in the act of antigen Presentation
Molecular Dynamics of Biomembranes, 1996Co-Authors: Tommy W. Nordeng, Anne Simonsen, Oddmund BakkeAbstract:Foreign antigen are internalized by antigen presenting cells and processed to peptides presented in the context of major histocompatibility complex (MHC) class II molecules to CD4+ T cells at the plasma membrane. Hence, class II molecules have to be sorted to endosomal compartments where they can meet and bind the antigenic peptides. The class II associated Invariant Chain contains sorting signals required for efficient class II accumulation in endosomes. Invariant Chain also has several other features contributing to the immune system’s specific combat of invaders.
Marvin M Van Luijn - One of the best experts on this subject based on the ideXlab platform.
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class ii associated Invariant Chain peptide as predictive immune marker in minimal residual disease in acute myeloid leukemia
OncoImmunology, 2014Co-Authors: Marvin M Van Luijn, Willemijn Van Den Ancker, Arjan A Van De LoosdrechtAbstract:The majority of patients with acute myeloid leukemia (AML) reach complete remission after high-dose chemotherapy. Still, half of these patients experience a relapse due to presence of minimal residual disease (MRD). Here we discuss the poor prognostic role of class II-associated Invariant Chain peptide (CLIP) expression on residual leukemic cells.
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tumor immune escape in acute myeloid leukemia class ii associated Invariant Chain peptide expression as result of deficient antigen presentation
OncoImmunology, 2012Co-Authors: Marvin M Van Luijn, Martine E D Chamuleau, Gert J Ossenkoppele, Arjan A Van De LoosdrechtAbstract:In this overview, we discuss the role of class II-associated Invariant Chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.
Idit Shachar - One of the best experts on this subject based on the ideXlab platform.
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Invariant Chain a Chain of command
Trends in Immunology, 2003Co-Authors: Didi Matza, Anat Kerem, Idit ShacharAbstract:Abstract Invariant Chain (Ii) is a type II integral membrane protein, which acts as a chaperone for MHC class II protein expression and facilitates antigen presentation. Recently, an additional role for Ii in the differentiation of immature to mature B cells has been described. These studies showed that Ii acts as a signaling molecule; its cytosolic domain induces B-cell maturation by activation of transcription mediated by the p65 member of the NF-κB family, a process that requires the B-cell-enriched coactivator, TAF II 105. NF-κB activation is mediated by the cytosolic region of Ii, which is liberated from the membrane. The process of intramembrane cleavage followed by nuclear translocation and transcriptional activation is reminiscent of regulated intramembrane cleavage (RIP). In this Review we suggest that the behavior of Ii shows remarkable similarities to the function of proteins processed by RIP and propose that the roles of Ii as a chaperone and as a signaling molecule are intertwined.
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preferential th1 immune response in Invariant Chain deficient mice
Journal of Immunology, 2002Co-Authors: Ian Topilski, Richard A Flavell, Alon Harmelin, Yoram Levo, Idit ShacharAbstract:MHC class II molecules associate with the Invariant Chain (Ii) molecule during biosynthesis. Ii facilitates the folding of class II molecules, interferes with their peptide association, and is involved in MHC class II transport. In this study, we have investigated the in vitro and in vivo immune response of Ii-deficient mice (Ii−/−). Our results have demonstrated that CD4+ T cells from Ii−/− mice proliferate normally in vitro after in vivo immunization with protein Ags. However, cytokine secretion profiles of Ag-primed CD4+ T cells from Ii−/− mice differ from CD4+ T cells from wild-type mice. Whereas cells from wild-type mice secrete IFN-γ and IL-4, cells from Ii−/− mice secrete mostly IFN-γ. Moreover, Ii−/− mice exhibit a normal Th1 response in the delayed-type hypersensitivity and trinitrobenzene sulfonic acid colitis models; however, these mice lack an in vivo Th2 response, as demonstrated in the asthma model. Therefore, we suggest that defective Ag presentation in Ii−/− mice leads selectively to a Th1 effector response.
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requirement for Invariant Chain in b cell maturation and function
Science, 1996Co-Authors: Idit Shachar, Richard A FlavellAbstract:Previously the role of Invariant Chain (Ii) had been described only as a chaperone that facilitates folding and transport of major histocompatability complex class II molecules; here it is shown that Ii is required for B cell development. B cells from mice lacking Ii were found to have a low response to T-independent type II antigen and could not proliferate after the mice were injected with antigen. Study of cell surface markers revealed a developmental arrest that prevented immature virgin B cells from becoming mature B cells in the periphery. This block was independent of major histocompatability complex class II expression and was an intrinsic feature of B cells that correlated with the amount of Ii. Thus, Ii participates by an unknown mechanism in B cell maturation.
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reconstitution of Invariant Chain function in transgenic mice in vivo by individual p31 and p41 isoforms
Immunity, 1995Co-Authors: Idit Shachar, Eileen A Elliott, Beth Chasnoff, Iqbal S Grewal, Richard A FlavellAbstract:Abstract MHC class II molecules associate with Invariant Chain (li) during biosynthesis. li facilitates folding of class II molecules, interferes with their association with peptides, and is involved in their transport. The murine li gene encodes two Chains, p31 and p41. The role of these isoforms has been studied in vitro only in inappropriate antigen-presenting cells. To circumvent this problem, we have generated Invariant Chain-deficient mice (Δli), which express exclusively the p31 and p41 isoforms. Low level expression of p31 or p41 is not sufficient for rescuing high levels of cell surface class II expression. However, low levels of the typical compact dimer conformation indicative of tight peptide binding are observed. Thus, both isoforms participate in class II folding and assembly. Furthermore, p31 and p41 retrieve the CD4+ T cell population, which is reduced in the (Δli) mice. Moreover, the immune response to protein antigen is restored by both isoforms.
