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  • 1
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    The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis (2013)
    BioMed Central
    Details
    Publication Date: 2013-10-04
    Description: Background: In apoptosis, proteolysis by caspases is the primary mechanism for both initiation and execution of programmed cell death (PCD). In contrast, the impact of proteolysis on the regulation and execution of caspase-independent forms of PCD (programmed necrosis, necroptosis) is only marginally understood. Likewise, the identity of the involved proteases has remained largely obscure. Here, we have investigated the impact of proteases in TNF-induced necroptosis. Results: The serine protease inhibitor TPKC protected from TNF-induced necroptosis in multiple murine and human cells systems whereas inhibitors of metalloproteinases or calpain/cysteine and cathepsin proteases had no effect. A screen for proteins labeled by a fluorescent TPCK derivative in necroptotic cells identified HtrA2/Omi (a serine protease previously implicated in PCD) as a promising candidate. Demonstrating its functional impact, pharmacological inhibition or genetic deletion of HtrA2/Omi protected from TNF-induced necroptosis. Unlike in apoptosis, HtrA2/Omi did not cleave another protease, ubiquitin C-terminal hydrolase (UCH-L1) during TNF-induced necroptosis, but rather induced monoubiquitination indicative for UCH-L1 activation. Correspondingly, pharmacologic or RNA interference-mediated inhibition of UCH-L1 protected from TNF-induced necroptosis. We found that UCH-L1 is a mediator of caspase-independent, non-apoptotic cell death also in diseased kidney podocytes by measuring cleavage of the protein PARP-1, caspase activity, cell death and cell morphology. Indicating a role of TNF in this process, podocytes with stably downregulated UCH-L1 proved resistant to TNF-induced necroptosis. Conclusions: The proteases HtrA2/Omi and UCH-L1 represent two key components of TNF-induced necroptosis, validating the relevance of proteolysis not only for apoptosis, but also for caspase-independent PCD. Since UCH-L1 clearly contributes to the non-apoptotic death of podocytes, interference with the necroptotic properties of HtrA2/Omi and UCH-L1 may prove beneficial for the treatment of patients, e.g. in kidney failure.
    Electronic ISSN: 1478-811X
    Topics: Biology , Medicine
    Published by BioMed Central
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  • 2
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    Down-regulation of the cancer/testis antigen 45 (CT45) is associated with altered tumor cell morphology, adhesion and migration (2013)
    BioMed Central
    Details
    Publication Date: 2013-06-11
    Description: Background: Due to their restricted expression in male germ cells and certain tumors, cancer/testis (CT) antigens are regarded as promising targets for tumor therapy. CT45 is a recently identified nuclear CT antigen that was associated with a severe disease score in Hodgkin's lymphoma and poor prognosis in multiple myeloma. As for many CT antigens, the biological function of CT45 in developing germ cells and in tumor cells is largely unknown. Methods: CT45 expression was down-regulated in CT45-positive Hodgkin's lymphoma (L428) fibrosarcoma (HT1080) and myeloma (U266B1) cells using RNA interference. An efficient CT45 knock-down was confirmed by immunofluorescence staining and/or Western blotting. These cellular systems allowed us to analyze the impact of CT45 down-regulation on proliferation, cell cycle progression, morphology, adhesion, migration and invasive capacity of tumor cells. Results: Reduced levels of CT45 did not coincide with changes in cell cycle progression or proliferation. However, we observed alterations in cell adherence, morphology and migration/invasion after CT45 down-regulation. Significant changes in the distribution of cytoskeleton-associated proteins were detected by confocal imaging. Changes in cell adherence were recorded in real-time using the xCelligence system with control and siRNA-treated cells. Altered migratory and invasive capacity of CT45 siRNA-treated cells were visualized in 3D migration and invasion assays. Moreover, we found that CT45 down-regulation altered the level of the heterogeneous nuclear ribonucleoprotein syncrip (hnRNP-Q1) which is known to be involved in the control of focal adhesion formation and cell motility. Conclusions: Providing first evidence of a cell biological function of CT45, we suggest that this cancer/testis antigen is involved in the modulation of cell morphology, cell adherence and cell motility. Enhanced motility and/or invasiveness of CT45-positive cells could contribute to the more severe disease progression that is correlated to CT45-positivity in several malignancies.
    Electronic ISSN: 1478-811X
    Topics: Biology , Medicine
    Published by BioMed Central
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  • 3
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    The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness (2018)
    Springer Nature
    Details
    Publication Date: 2018
    Print ISSN: 1529-2908
    Electronic ISSN: 1529-2916
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 4
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    Analysis of intestinal microbiota in hybrid house mice reveals evolutionary divergence in a vertebrate hologenome (2015)
    Springer Nature
    Details
    Publication Date: 2015-03-06
    Description: Article Animal hosts and their associated microbes are largely the outcome of coevolution. Here, the authors show differences in the intestinal microbiome of hybrids compared with pure species of house mice, which suggests that host–microbiome interactions contribute to the evolution of host species. Nature Communications doi: 10.1038/ncomms7440 Authors: Jun Wang, Shirin Kalyan, Natalie Steck, Leslie M. Turner, Bettina Harr, Sven Künzel, Marie Vallier, Robert Häsler, Andre Franke, Hans-Heinrich Oberg, Saleh M. Ibrahim, Guntram A. Grassl, Dieter Kabelitz, John F. Baines
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 5
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    Recent advances in γδ T cell biology: New ligands, new functions, and new translational perspectives (2021)
    Frontiers Media SA
    Details
    Publication Date: 2023-12-21
    Description: Gamma/delta (γδ) T-cells are a small subset of T-lymphocytes in the peripheral circulation but constitute a major T-cell population at other anatomical localizations such as the epithelial tissues. In contrast to conventional a/ß T-cells, the available number of germline genes coding for T-cell receptor (TCR) variable elements of γδ T-cells is very small. Moreover, there is a prefential localization of γδ T-cells expressing given Vgamma and Vdelta genes in certain tissues. In humans, γδ T-cells expressing the Vg9Vd2-encoded TCR account for anywhere between 50 and 〉95% of peripheral blood γδ T-cells, whereas cells expressing non-Vd2 genes dominate in mucosal tissues. In mice, there is an ordered appearance of γδ T-cell „waves“ during embryonic development, resulting in preferential localization of γδ T-cells expressing distinct VgammaVdelta genes in the skin, the reproductive organs, or gut epithelia. The major function of γδ T-cells resides in local immunosurveillance and immune defense against infection and malignancy. This is supported by the identification of ligands that are selectively recognized by the γδ TCR. As an example, human Vgamma9Vdelta2 T-cells recognize phosphorylated metabolites („phosphoantigens“) that are secreted by many pathogens but can also be overproduced by tumor cells, providing a basis for a role of these γδ T-cells in both anti-infective and anti-tumor immunity. Similarly, the recognition of endothelial protein C receptor by human non-Vdelta2 γδ T-cells has recently been identified to provide a link for the role for such γδ T-cells in immunity against epithelial tumor cells and cytomegalovirus-infected endothelial cells. In addition to „classical“ functions such as cytokine production and cytotoxicity, recent studies suggest that subsets of γδ T-cells can exert additional functions such as regulatory activity and – quite surpisingly – „professional“ antigen-presenting capacity. It is currently not well known how this tremendous extent of functional plasticity is regulated and what is the extent of γδ TCR ligand diversity. Due to their non-MHC-restricted recognition of unusual stress-associated ligands, γδ T-cells have raised great interest as to their potential translational application in cell-based immunotherapy. Topics of this Research Focus include: Molecular insights into the activation and differentiation requirements of γδ T-cells, role of pyrophosphates and butyrophilin molecules for the activation of human γδ T-cells, role of γδ T-cells in tumor immunity and in other infectious and non-infectious diseases, and many others. We are most grateful to all colleagues who agreed to write a manuscript. Thanks to their contributions, this E-book presents an up-to-date overview on many facets of the still exciting γδ T-cells.
    Keywords: R5-920 ; RC581-607 ; Infection ; Butyrophilin 3A1 ; Tumor-infiltrating lymphocytes ; cancer immunotherapy ; IL-17 ; Pyrophosphates ; bic Book Industry Communication::M Medicine
    Language: English
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    E-BOOK
  • 6
    Electronic Resource
    Electronic Resource
    Analysis of the Human T-Cell Receptor Vγ Gene Usage by Flow Cytometry (1995)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 756 (1995), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1995.tb44491.x
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  • 7
    Electronic Resource
    Electronic Resource
    Mouse T-cell receptor variable gene segment families (1995)
    Springer
    Immunogenetics 42 (1995), S. 501-530 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract All mouse T-cell receptor α/δ, β, and γ variable (Tcra/d, b-, and g-V) gene segments were aligned to compare the sequences with one another, to group them into subfamilies, and to derive a name which complies with the standard nomenclature. It was necessary to change the names of some V gene segments because they conflicted with those of other segments. The traditional classification into subfamilies was re-evaluated using a much larger pool of sequences. In the mouse, most V gene segments can be grouped into subfamilies of closely related genes with significantly less similarity between different subfamilies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172177
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  • 8
    Electronic Resource
    Electronic Resource
    Human T-cell receptor variable gene segment families (1995)
    Springer
    Immunogenetics 42 (1995), S. 455-500 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Multiple DNA and protein sequence alignments have been constructed for the human T-cell receptor α/δ, β, and γ (TCRA/D, B, and G) variable (V) gene segments. The traditional classification into subfamilies was confirmed using a much larger pool of sequences. For each sequence, a name was derived which complies with the standard nomenclature. The traditional numbering of V gene segments in the order of their discovery was continued and changed when in conflict with names of other segments. By discriminating between alleles at the same locus versus genes from different loci, we were able to reduce the number of more than 150 different TCRBV sequences in the database to a repertoire of only 47 functional TCRBV gene segments. An extension of this analysis to the over 100 TCRAV sequences results in a predicted repertoire of 42 functional TCRAV gene segments. Our alignment revealed two residues that distinguish between the highly homologous Vδ and Vα, one at a site that in VH contacts the constant region, the other at the interface between immunoglobulin VH and VL. This site may be responsible for restricted pairing between certain Vδ and Vγ chains. On the other hand, Vβ and Vγ appear to be related by the fact that their CDR2 legnth is increased by four residues as compared with that of Vα/δ peptides.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172176
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  • 9
    Electronic Resource
    Electronic Resource
    Comparison of human and mouse T-cell receptor variable gene segment subfamilies (1995)
    Springer
    Immunogenetics 42 (1995), S. 531-540 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Like the immunoglobulin Igh-V and Igk-V gene families, the human or mouse TCRV gene families may be grouped into subfamilies displaying 〉75% nucleic acid sequence similarity among their members. Systematic interspecies sequence comparisons reveal that most mouse Tcr-V subfamilies exhibit clear homology to human TCRV subfamilies (〉60% amino acid sequence similarity). Homologous pairs of TCRV genes in mice and humans show higher sequence similarity than TCRV genes from different subfamilies within either species, indicating transpecies evolution of TCRV genes. Mouse and human homologues show conservation of their relative map order, particularly in the 3' region and a similar sequential and developmentally programmed expression. When the V regions from both species were analyzed together, local length differences and conserved residues in the loop regions were revealed, characteristic of each of the four TCRV families.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172178
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  • 10
    Electronic Resource
    Electronic Resource
    Regulation of activation-induced cell death of mature T-lymphocyte populations (2000)
    Springer
    Cell & tissue research 301 (2000), S. 85-99 
    Details
    ISSN: 1432-0878
    Keywords: Activation-induced cell death Apoptosis Immune regulation Programmed cell death T lymphocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Resting mature T lymphocytes are activated when triggered via their antigen-specific T-cell receptor (TCR) to elicit an appropriate immune response. In contrast, preactivated T cells may undergo activation-induced cell death (AICD) in response to the same signals. Along with cell death induced by growth factor deprivation, AICD followed by the elimination of useless or potentially harmful cells preserves homeostasis, leads to the termination of cellular immune responses and ensures peripheral tolerance. T-cell apoptosis and AICD are controlled by survival cytokines such as interleukin-2 (IL-2) and by death factors such as tumor necrosis factor (TNF) and CD95 ligand (CD95L). In AICD-sensitive T cells, stimulation upregulates expression of one or several death factors, which in turn engage specific death receptors on the same or a neighboring cell. Death receptors are activated by oligomerization to rapidly assemble a number of adapter proteins and enzymes to result in an irreversible activation of proteases and nucleases that culminates in cell death by apoptosis. Increased knowledge of the molecular mechanisms that regulate AICD of lymphocytes opens new immunotherapeutic perspectives for the treatment of certain autoimmune diseases, and has implications in other areas such as transplantation medicine and AIDS research.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004419900155
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