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  • 1
    Keywords: PEPTIDE ; RECEPTOR ; CELLS ; EXPRESSION ; Germany ; PROTEIN ; DRUG ; MOLECULES ; LINES ; MICE ; COMPLEX ; murine ; primary ; ANTIGEN ; ANTIGENS ; BIOSYNTHESIS ; LYMPHOCYTES ; antigen presentation ; B-CELLS ; CLASS-II MOLECULES ; EXCHANGE ; H2-O ; HLA-DM ; HLA-DO ; IA MOLECULES ; INVARIANT CHAIN ; MHC MOLECULES ; MONOCLONAL- ANTIBODY ; PEPTIDE REPERTOIRE ; PEPTIDES ; T- CELLS
    Abstract: Peptide loading onto MHC class II molecules takes place in endosomal compartments along the endocytic pathway. There, loading is facilitated by the catalytic function of the accessory molecule H2-M, which helps to exchange the invariant chain-derived CLIP peptide in the groove of class II molecules for antigenic peptide. H2-O is another accessory molecule specific to the class II pathway, which is found tightly associated with H2-M and selectively expressed in B cells. Using stable H2-O ribozyme-antisense transfectants, H2-O overexpressing murine B cell lines, and H2-O-transgenic mice, we investigated the effects of H2-O on antigen presentation. The results show that presentation of a variety of exogenous protein antigens to a panel of T cell hybridomas depended on the levels of H2-O in the antigenpresenting B cells. Thus, increased H2-O expression downmodulated, whereas reduced H2-O levels, enhanced presentation. Presentation of endogenous antigen was also diminished by H2-O. Despite the pronounced effects on antigen presentation, the mass spectrometric profiles of peptides eluted from A(b) molecules were very similar in cells expressing different H2-O levels. The intracellular location of H2-O inhibitory activity was investigated with the drug chloroquine, which prevents acidification of the endocytic pathway. The observations indicate that H2-O predominantly inhibits antigen presentation in early endosomal compartments. Thus, H2-O appears to skew peptide loading to late endosomal/lysosomal compartments. This may favor presentation of antigens taken up by the B cell receptor
    Type of Publication: Journal article published
    PubMed ID: 12645938
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  • 2
    Keywords: OPTIMIZATION ; PEPTIDE ; SPECTRA ; CELLS ; EXPRESSION ; INHIBITOR ; Germany ; PROTEIN ; PROTEINS ; MOLECULES ; MICE ; ACTIVATION ; COMPLEX ; COMPLEXES ; murine ; MEMBER ; MHC ; LYMPHOCYTES ; antigen presentation ; PEPTIDES ; STABILITY ; MHC class I ; DEGRADATION ; SUBUNITS ; TRANSLOCATION ; antigen processing ; CELL-LINE .220 ; HISTOCOMPATIBILITY COMPLEX ; LOADING COMPLEX ; MUTANT MICE ; NEWLY SYNTHESIZED PROTEINS
    Abstract: Tapasin is a member of the MHC class I loading complex where it bridges the TAP peptide transporter to class I molecules. The main role of tapasin is assumed to be the facilitation of peptide loading and optimization of the peptide cargo. Here, we describe another important function for tapasin. In tapasin- deficient (Tpn(-/-)) mice the absence of tapasin was found to have a dramatic effect on the stability of the TAP1/TAP2 heterodimeric peptide transporter. Steady-state expression of TAP protein was reduced more than 100-fold from about 3 x 10(4) TAP molecules per wild-type splenocyte to about 1 x 10(2) TAP per Tpn(-/-) splenocyte. Thus, a major function of murine tapasin appears to be the stabilization of TAR The low amount of TAP molecules in Tpn(-/-) lymphocytes is likely to contribute to the severe impairment of MHC class I expression. Surprisingly, activation of Tpn(-/-) lymphocytes yielded strongly enhanced class I expression comparable to wild-type levels, although TAP expression remained low and in the magnitude of several hundred molecules per cell. The high level of class I on activated Tpn(-/-) cells depended on peptides generated by the proteasome as indicated by blockade with the proteasome-specific inhibitor lactacystin. Lymphocyte activation induced an increase in ubiquitinated proteins that are cleaved into peptides by the proteasome. These findings suggest that in the presence of a large peptide pool in the cytosol, a small number of TAP transporters is sufficient to translocate enough peptides for high class I expression. However, these class I molecules were less stable than those of wild-type cells, indicating that tapasin is not only required for stabilization of TAP but also for optimization of the spectrum of bound peptides
    Type of Publication: Journal article published
    PubMed ID: 12594855
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  • 3
    Keywords: CELLS ; proliferation ; BLOOD ; CELL ; Germany ; human ; DISEASE ; DISEASES ; GENE-EXPRESSION ; ACTIVATION ; RESPONSES ; CELL ACTIVATION ; IFN-GAMMA ; ANTIGEN ; ANTIGENS ; autoimmune diseases ; AUTOIMMUNE-DISEASE ; CONTRAST ; SELF-ANTIGENS ; T cell ; T cell activation ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; MEMORY ; STIMULATION ; GLYCOPROTEIN ; SWEDEN ; PHENOTYPE ; allogeneic ; INDIVIDUALS ; specificity ; PERIPHERAL-BLOOD ; HEALTHY ; MULTIPLE-SCLEROSIS ; rodent ; HUMAN BLOOD ; AUTOANTIGEN ; AUTOIMMUNE ENCEPHALOMYELITIS ; CD25(+) regulatory T cell ; cord blood ; myelin oligodendrocyte glycoprotein ; SELF ; SUBPOPULATION ; THYMOCYTES
    Abstract: Regulatory T cells expressing CD25 have been shown to protect rodents from organ-specific autoimmune diseases. Similar CD25(+) cells with a memory phenotype exerting suppressive function after polyclonal or allogeneic stimulation are also present in adult human blood. We demonstrate that adult human CD25(+) cells regulate the response to myelin oligodendrocyte glycoprotein (MOG), as depletion of CD25(+) cells increases response,; of PBMC and the addition of purified CD25(+) cells suppresses MOG-specific proliferation and IFN-gamma production of CD4(+)CD25(-) T cells. In contrast, cord blood CD25(+) cells do not inhibit responses to self antigens, and only a small subpopulation of cord CD25(+) cells expresses the typical phenotype of adult regulatory T cells (CD45RA(-) and GITR(+)) enabling suppression of polyclonal responses. We conclude that activation of self-reactive T cells in normal healthy individuals is prevented by the presence of self-antigen-specific CD25+ regulatory T cells and that the majority of these cells mature after birth
    Type of Publication: Journal article published
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  • 4
    Keywords: ENVIRONMENT ; ANGIOGENESIS ; CANCER ; CELLS ; tumor ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; GENERATION ; DISTINCT ; PATIENT ; RESPONSES ; INDUCTION ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; LYMPH-NODES ; treatment ; tumor antigens ; MOUSE ; MALIGNANCIES ; resistance ; CANCER-PATIENTS ; IMMUNITY ; IMMUNOTHERAPY ; MOUSE MODEL ; REJECTION ; DE-NOVO ; CANCER PATIENTS ; CANCER-THERAPY ; EFFECTOR ; cancer therapy ; SOLID TUMORS ; T-CELL-ACTIVATION ; ANTIGENIC CANCER-CELLS ; ANTITUMOR LYMPHOCYTES ; EFFECTOR FUNCTION ; immune therapy ; transgenic tumor models ; TUMOR-ANTIGENS
    Abstract: In immunological cancer therapy, the current treatment emphasis is on the generation of effector cells that are specific for tumor antigens. However, there is a distressing lack of correlation between the induction of specific immunity in cancer patients and measurable clinical benefit. By studying mouse models of de novo tumongenesis we are beginning to understand that the tumor itself, in particular the manifestation of a distinct tumor environment, impairs immune effector function; this concept is yet to be applied in human malignancy
    Type of Publication: Journal article published
    PubMed ID: 15368278
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  • 5
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; INHIBITION ; VIVO ; DISEASE ; SITE ; SITES ; GENE ; transcription ; DIFFERENTIATION ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; TRANSCRIPTION FACTOR ; AP-1 ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; PROMOTER ; BETA ; immune response ; IMMUNE-RESPONSE ; LIVING CELLS ; CD28 ; C-REL ; T lymphocyte,transcription factor,cytokine
    Abstract: IL-4 plays a pivotal role in the development of the Th2 cell mediated humoral immune response and causes IgE-dependent allergic inflammatory diseases. Expression of IL-4 in differentiated Th2 cells is regulated by transcription factors such as NF-AT AP-1 and NF-IL6. Recently, increasing evidence indicates that the pro-inflammatory transcription factor NF-kappaB,13 may also participate in IL-4 expression. In this study, we show that the IL-4 promoter is synergistically activated by NF-kappaB, NF-AT and NF-IL6 at the NF-kappaB/NF-AT/NF-IL6 composite sites. In addition, we performed the chromatin immunoprecipitation technique to determine the functional relevance of NF-kappaB in the activation of the IL-4 gene in vivo. We demonstrate that NF-kappaB binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappaB nuclear translocation in living cells blocked binding of NF-kappaB to the IL-4 promoter. The data provide first evidence that NF-kappaB is directly involved in IL-4 transcription
    Type of Publication: Journal article published
    PubMed ID: 15048722
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  • 6
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; Germany ; IN-VIVO ; PATHWAY ; SYSTEM ; SYSTEMS ; liver ; EFFICIENCY ; MICE ; ACTIVATION ; IFN-GAMMA ; INDUCTION ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; T-CELL ; T-CELLS ; TOLERANCE ; BONE-MARROW ; MATURATION ; knockout ; MOUSE ; LINE ; DEGRADATION ; IMMUNITY ; NAIVE ; CYTOTOXICITY ; CROSS-PRESENTATION ; endothelial cells ; PH ; development ; KNOCKOUT MICE ; CYTOKINE PRODUCTION ; CELL TOLERANCE ; dendritic cell ; INDUCE ; T cell tolerance ; KUPFFER CELLS ; ADOPTIVE TRANSFER ; CD8 T cell tolerance ; ENDOTOXIN ; oral tolerance ; scavenger endothelial cells
    Abstract: After ingestion, oral antigens distribute systemically and provoke T cell stimulation outside the gastrointestinal tract. Within the liver, scavenger liver simisoidal endothelial cells (LSEC) eliminate blood-borne antigens and induce T cell tolerance. Here we investigated whether LSEC contribute to oral tolerance. Oral antigens were efficiently cross-presented on H-2k(b) by LSEC to naive CD8 T cells. Cross-presentation efficiency in LSEC but not dendritic cells was increased by antigen-exposure to heat or low pH. Mechanistically, cross-presentation in LSEC requires endosomal maturation, involves hsc73 and proteasomal degradation. H-2k(b)-restricted cross-presentation of oral antigens by LSEC in vivo induced CD8 T cell priming and led to development of CD8 T cell tolerance in two independent experimental systems. Adoptive transfer of LSEC from mice fed with antigen (ovalbumin) into RAG2(-/-) knockout mice, previously reconstituted with naive ovalbumin-specific CD8 T cells, prevented development of specific cytotoxicity and expression of IFN-gamma in CD8 T cells. Using a new transgenic mouse line expressing H-2k(b) only on endothelial cells, we have demonstrated that oral antigen administration leads to tolerance in H-2K(b)-restricted CD8 T cells. Collectively, our data demonstrate a participation of the liver, in particular scavenger LSEC, in development of CD8 T cell tolerance towards oral antigens
    Type of Publication: Journal article published
    PubMed ID: 16163670
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  • 7
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VIVO ; MICE ; LIGAND ; FAMILY ; CONTRAST ; BINDING ; treatment ; MOLECULE ; ALPHA ; ACID ; GLYCOPROTEIN ; ADHESION ; MUSCLE ; FRAGMENTS ; LECTIN ; INTERACTS ; P-SELECTIN ; CHILDREN ; TNF-ALPHA ; inflammation ; C-type lectin ; NEUTROPHILS ; FAMILIES ; RESIDUES ; DEFICIENT MICE ; carbohydrate structures ; GLYCOPROTEINS ; INTEGRINS ; function ; in vivo ; FRAGMENT ; ENDOTHELIAL-CELL ; carbohydrate ; ACID-RESIDUES ; GLYCOPROTEIN LIGAND-1 ; HIGH ENDOTHELIAL VENULES ; LYMPHOCYTE RECIRCULATION ; ROLLING IN-VIVO ; TYROSINE SULFATION
    Abstract: L-selectin belongs to the C-type lectin family of glycoproteins and is constitutively expressed on most leukocytes. L-selectin mediates leukocyte rolling in inflamed microvessels and high endothelial venules (HEV) via binding to specific carbohydrate structures on selectin ligands. Previous studies using sialidase treatment suggested a role of sialic acid residues in L-selectin-dependent rolling. To investigate the role of the alpha 2,3-sialyltransferase (ST3Gal)-IV on L-selectin ligand activity in vivo, we studied leukocyte rolling in inflamed venules of the cremaster muscle and in Peyer's patch HEV of ST3Gal-IV-deficient mice and littermate control mice. In cremaster muscle venules with or without TNF-alpha treatment, L-selectin-dependent rolling was almost completely abolished in ST3Gal-IV-/- mice. In both models, L-selectin interacts with P-selectin glycoprotein ligand-1 (PSGL-1) presented by adherent leukocytes and leukocyte fragments, but not with endothelial L-selectin ligands. In contrast, L-selectin-dependent rolling in Peyer's patch HEV, which is mediated by unknown endothelial L-selectin ligands, was not impaired in the absence of ST3Gal-IV. Our in vivo data show that PSGL-1, the molecule responsible for L-selectin-mediated leukocyte interactions in inflammation, is dependent on ST3Gal-IV, while alpha 2,3-sialylation by ST3Gal-IV is not necessary for L-selectin ligand activity on high endothelial cells of Peyer's patch HEV
    Type of Publication: Journal article published
    PubMed ID: 17111351
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  • 8
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; MICE ; ACTIVATION ; RESPONSES ; DNA ; INDUCTION ; LYMPH-NODES ; oligonucleotides ; TOLL-LIKE RECEPTORS ; IMMUNE SUPPRESSION ; CATABOLISM ; LYMPH-NODE ; INDOLEAMINE 2,3-DIOXYGENASE ; BACTERIAL-DNA ; EXPANSION ; indoleamine 2,3-dioxygenase (IDO) ; local and systemic immunity ; MURINE DENDRITIC CELLS ; TRYPTOPHAN DEGRADATION
    Abstract: CpG-rich oligonucleotides (CpG-ODN) bind to Toll-like receptor 9 (TLR9) and are used as powerful adjuvants for vaccination. Here we report that CpG-ODN not only act as immune stimulatory agents but can also induce strong immune suppression depending on the anatomical location of application. In agreement with the adjuvant effect, subcutaneous application of antigen plus CpG-ODN resulted in antigen-specific T cell activation in local lymph nodes. In contrast, systemic application of CpG-ODN resulted in suppression of T cell expansion and CTL activity in the spleen. The suppressive effect was mediated by indoleamine 2,3-dioxygenase (IDO) as indicated by the observation that CpG-ODN induced IDO in the spleen and that T cell suppression could be abrogated by 1-methyl-tryptophan (1-MT), an inhibitor of IDO. No expression of IDO was observed in lymph nodes after injection of CpG-ODN, explaining why suppression was restricted to the spleen. Studies with a set of knockout mice demonstrated that the CpG-ODN-induced immune suppression is dependent on TLR9 stimulation and independent of type I and type II interferons. The present study shows that for the use of CpG-ODN as an adjuvant in vaccines, the route of application is crucial and needs to be considered. In addition, the results indicate that down-modulation of immune responses by CpG-ODN may be possible in certain pathological conditions
    Type of Publication: Journal article published
    PubMed ID: 16323249
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  • 9
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; POPULATION ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; QUALITY ; ANTIGEN ; ANTIGENS ; T cell ; T-CELL ; DYNAMICS ; BIOLOGY ; FORM ; MOUSE ; gene expression ; QUALITY-CONTROL ; DISPLAY ; EPITHELIAL-CELLS ; ESTABLISHMENT ; microenvironment ; SUBSETS ; HETEROGENEITY ; IMPLEMENTATION ; SUBSET ; RE ; regulation ; AIRE ; STRATIFIED EPITHELIA ; progenitor ; immunology ; PRECURSOR ; promiscuous gene expression ; EMERGENCE ; central tolerance ; MURINE THYMUS ; NEONATAL THYMECTOMY ; thymic epithelial cells ; TURNOVER
    Abstract: Thymic epithelial cells (TEC) form the structural and functional microenvironment necessary for the establishment and quality control of the T cell repertoire. In addition, they provide an ectopic source of numerous tissue-restricted antigens (TRA), a feature called promiscuous gene expression (pGE). How the regulation of pGE is related to the cell biology of TEC subset(s), e.g. their turnover and developmental interrelationship is still poorly understood. The observation that pGE is foremost a property of phenotypically and functionally mature medullary TEC (mTEC) implies that the full implementation of pGE is contingent on mTEC differentiation. Here, we show that the emergence of TEC subsets and pGE is tightly correlated during ontogeny and we provide evidence that mature CD80(Pos) mTEC develop from an immature CD80(neg) subset. This differentiation step proceeds. continuously in the postnatal thymus. While mature mTEC turnover in 2 to 3 weeks, immature mTEC encompass a smaller cycling and a larger non-cycling pool. The latter might serve as a reservoir of committed precursors, which sustain this renewal process. Our data document that mTEC represent a highly dynamic cell population, and they imply that the availability and display of TRA in the thymus undergoes a perpetual temporal and spatial reorganization
    Type of Publication: Journal article published
    PubMed ID: 18000951
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  • 10
    Keywords: RECEPTOR ; CELLS ; proliferation ; SURVIVAL ; CELL ; Germany ; IN-VIVO ; MODEL ; VIVO ; SUPPORT ; MICE ; TIME ; ACTIVATION ; LIGAND ; CD8(+) T-CELLS ; DENDRITIC CELLS ; chromosome ; MOUSE ; ACQUISITION ; PROMOTER ; EFFICIENT ; LYMPHOCYTES ; NATURAL-KILLER-CELLS ; NK cells ; MOUSE MODEL ; REVEALS ; IN-VIVO DEPLETION ; ORDER ; RE ; ABLATION ; LIFE ; dendritic cell ; immunology ; HOMEOSTASIS ; bacterial ; response ; NATURAL-KILLER-CELL ; BACTERIAL ARTIFICIAL CHROMOSOME ; KILLER-CELLS ; natural killer ; Natural killer cells ; NK-CELLS ; Diphtheria toxin receptor ; IL-15 ; INTERLEUKIN-15
    Abstract: Dendritic cells (DC) are known to support the activation of natural killer (NK) cells. However, little is known about the role for DC in NK-cell homeostasis. In order to investigate this question, a novel bacterial artificial chromosome transgenic mouse model was generated in which the diphtheria toxin receptor is expressed under the CD11c promoter. In these mice efficient DC depletion can be achieved over prolonged periods of time by multiple injections of diphtheria toxin. We show here that NK cells require DC for full acquisition of effector function in vivo in response to the bacterial-derived TLR ligand CpG. Importantly, DC were found to play an instrumental role for maintaining normal homeostasis of NK cells. This is achieved by IL-15 production by DC, which supports the homeostatic proliferation of NK cells
    Type of Publication: Journal article published
    PubMed ID: 18825750
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