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  • 1
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    Online Resource
    Ligand-dependent Inhibition of CD1d-restricted NKT Cell Development in Mice Transgenic for the Activating Receptor Ly49D
    Rockefeller University Press ; 2003
    In:  The Journal of Experimental Medicine Vol. 197, No. 7 ( 2003-04-07), p. 919-925
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 197, No. 7 ( 2003-04-07), p. 919-925
    Abstract: In addition to their CD1d-restricted T cell receptor (TCR), natural killer T (NKT) cells express various receptors normally associated with NK cells thought to act, in part, as modulators of TCR signaling. Immunoreceptor-tyrosine activation (ITAM) and inhibition (ITIM) motifs associated with NK receptors may augment or attenuate perceived TCR signals respectively, potentially influencing NKT cell development and function. ITIM-containing Ly49 family receptors expressed by NKT cells are proposed to play a role in their development and function. We have produced mice transgenic for the ITAM-associated Ly49D and ITIM-containing Ly49A receptors and their common ligand H2-Dd to determine the importance of these signaling interplays in NKT cell development. Ly49D/H2-Dd transgenic mice had selectively and severely reduced numbers of thymic and peripheral NKT cells, whereas both ligand and Ly49D transgenics had normal numbers of NKT cells. CD1d tetramer staining revealed a blockade of NKT cell development at an early precursor stage. Coexpression of a Ly49A transgene partially rescued NKT cell development in Ly49D/H2-Dd transgenics, presumably due to attenuation of ITAM signaling. Thus, Ly49D-induced ITAM signaling is incompatible with the early development of cells expressing semi-invariant CD1d-restricted TCRs and appropriately harmonized ITIM–ITAM signaling is likely to play an important role in the developmental program of NKT cells.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20021615
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2003
    detail.hit.zdb_id: 1477240-1
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  • 2
    Online Resource
    Online Resource
    Ly49D Engagement on T Lymphocytes Induces TCR-Independent Activation and CD8 Effector Functions That Control Tumor Growth
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 1 ( 2009-01-01), p. 183-192
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 1 ( 2009-01-01), p. 183-192
    Abstract: Recent data showing expression of activating NK receptors (NKR) by conventional T lymphocytes raise the question of their role in the triggering of TCR-independent responses that could be damaging for the host. Transgenic mice expressing the activating receptor Ly49D/DAP12 offer the opportunity to better understand the relevance of ITAM signaling in the biology of T cells. In vitro experiments showed that Ly49D engagement on T lymphocytes by a cognate MHC class I ligand expressed by Chinese hamster ovary (CHO) cells or by specific Ab triggered cellular activation of both CD4 and CD8 populations with modulation of activation markers and cytokine production. The forced expression of the ITAM signaling chain DAP12 is mandatory for Ly49D-transgenic T cell activation. In addition, Ly49D stimulation induced T lymphocyte proliferation, which was much stronger for CD8 T cells. Phenotypic analysis of anti-Ly49D-stimulated CD8 T cells and their ability to produce high levels of IFN-γ and to kill target cells indicate that Ly49D ligation generates effector cytotoxic CD8 T cells. Ly49D engagement by itself also triggered cytotoxic activity of activated CD8 T cells. Adoptive transfer experiments confirmed that Ly49D-transgenic CD8 T cells are able to control growth of CHO tumor cells or RMA cells transfected with Hm1-C4, the Ly49D ligand normally expressed by CHO. In conclusion, Ly49D engagement on T cells leads to T cell activation and to a full range of TCR-independent effector functions of CD8 T cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.1.183
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Ly49D-Mediated ITAM Signaling in Immature Thymocytes Impairs Development by Bypassing the Pre-TCR Checkpoint
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 187, No. 1 ( 2011-07-01), p. 110-117
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 1 ( 2011-07-01), p. 110-117
    Abstract: Activating and inhibitory NK receptors regulate the development and effector functions of NK cells via their ITAM and ITIM motifs, which recruit protein tyrosine kinases and phosphatases, respectively. In the T cell lineage, inhibitory Ly49 receptors are expressed by a subset of activated T cells and by CD1d-restricted NKT cells, but virtually no expression of activating Ly49 receptors is observed. Using mice transgenic for the activating receptor Ly49D and its associated ITAM signaling DAP12 chain, we show in this article that Ly49D-mediated ITAM signaling in immature thymocytes impairs development due to a block in maturation from the double negative (DN) to double positive (DP) stages. A large proportion of Ly49D/DAP12 transgenic thymocytes were able to bypass the pre-TCR checkpoint at the DN3 stage, leading to the appearance of unusual populations of DN4 and DP cells that lacked expression of intracellular (ic) TCRβ-chain. High levels of CD5 were expressed on ic TCRβ− DN and DP thymocytes from Ly49D/DAP12 transgenic mice, further suggesting that Ly49D-mediated ITAM signaling mimics physiological ITAM signaling via the pre-TCR. We also observed unusual ic TCRβ− single positive thymocytes with an immature CD24high phenotype that were not found in the periphery. Importantly, thymocyte development was completely rescued by expression of an Ly49A transgene in Ly49D/DAP12 transgenic mice, indicating that Ly49A-mediated ITIM signaling can fully counteract ITAM signaling via Ly49D/DAP12. Collectively, our data indicate that inappropriate ITAM signaling by activating NK receptors on immature thymocytes can subvert T cell development by bypassing the pre-TCR checkpoint.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1002755
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    Isolation and characterisation of zona pellucida A (ZPA) cDNAs from two species of marsupial: regulated oocyte-specific expression of ZPA transcripts
    Cambridge University Press (CUP) ; 1999
    In:  Zygote Vol. 7, No. 3 ( 1999-08), p. 239-248
    Details
    In: Zygote, Cambridge University Press (CUP), Vol. 7, No. 3 ( 1999-08), p. 239-248
    Abstract: The zona pellucida (ZP) is an extracellular glycoprotein coat that is deposited around the oocyte during folliculogenesis and performs several functions that relate to fertilisation and preimplantion development. In eutherian mammals it consists of three major glycoproteins – ZPA, ZPB, and ZPC – but little is known about its molecular constitution in marsupials. We have isolated the cDNA encoding the ZPA homologue in two distantly related marsupial series: the possum, Trichosurus vulpecula (a phalangerid) and the dunnart Sminthopsis crassicaudata (a dasyurid). The two cDNA sequences were 86% identical and showed extensive regions of homology to eutherian ZPA proteins, particularly in the central region of the molecule. Many other features of the ZPA protein, except the positioning of the N -linked glycosylation sites, were also conserved between marsupials and eutherians. ZPA expression was shown to occur maximally in the cytoplasm of the oocyte primary follicles with a little, but significant, expression in oocytes of both primordial follicles and in the cytoplasm of the oocyte in follicles with an antral cavity. No expression was seen in surrounding follicle or granulosa cells
    Type of Medium: Online Resource
    ISSN: 0967-1994 , 1469-8730
    URL: Article
    DOI: 10.1017/S0967199499000623
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 1999
    detail.hit.zdb_id: 1483381-5
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Intracellular and Extracellular Leukemia Inhibitory Factor Proteins Have Different Cellular Activities That Are Mediated by Distinct Protein Motifs
    American Society for Cell Biology (ASCB) ; 2000
    In:  Molecular Biology of the Cell Vol. 11, No. 4 ( 2000-04), p. 1369-1383
    Details
    In: Molecular Biology of the Cell, American Society for Cell Biology (ASCB), Vol. 11, No. 4 ( 2000-04), p. 1369-1383
    Abstract: Although many growth factors and cytokines have been shown to be localized within the cell and nucleus, the mechanism by which these molecules elicit a biological response is not well understood. The cytokine leukemia inhibitory factor (LIF) provides a tractable experimental system to investigate this problem, because translation of alternatively spliced transcripts results in the production of differentially localized LIF proteins, one secreted from the cell and acting via cell surface receptors and the other localized within the cell. We have used overexpression analysis to demonstrate that extracellular and intracellular LIF proteins can have distinct cellular activities. Intracellular LIF protein is localized to both nucleus and cytoplasm and when overexpressed induces apoptosis that is inhibited by CrmA but not Bcl-2 expression. Mutational analysis revealed that the intracellular activity was independent of receptor interaction and activation and reliant on a conserved leucine-rich motif that was not required for activation of cell surface receptors by extracellular protein. This provides the first report of alternate intracellular and extracellular cytokine activities that result from differential cellular localization of the protein and are mediated by spatially distinct motifs.
    Type of Medium: Online Resource
    ISSN: 1059-1524 , 1939-4586
    URL: Article
    DOI: 10.1091/mbc.11.4.1369
    Language: English
    Publisher: American Society for Cell Biology (ASCB)
    Publication Date: 2000
    detail.hit.zdb_id: 1474922-1
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Complex Conserved Organization of the Mammalian Leukemia Inhibitory Factor Gene: Regulated Expression of Intracellular and Extracellular Cytokines
    The American Association of Immunologists ; 1999
    In:  The Journal of Immunology Vol. 162, No. 8 ( 1999-04-15), p. 4637-4646
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 162, No. 8 ( 1999-04-15), p. 4637-4646
    Abstract: Leukemia inhibitory factor (LIF) is a member of the IL-6 family of pleiotropic cytokines, which are extensively involved in modulating hematopoiesis and immunity. We have undertaken a detailed analysis of LIF genomic organization and gene transcription and investigated the proteins expressed from alternate transcripts. Previously unidentified LIF transcripts, containing alternate first exons spliced onto common second and third exons, were cloned from murine embryonic stem cells, human embryonal carcinoma cells, and primary porcine fibroblasts. Based on sequence homology and position within the genomic sequence, this confirmed the existence of the LIF-M transcript in species other than the mouse and identified a new class of transcript, designated LIF-T. Thus, a complex genomic organization of the LIF gene, conserved among eutherian mammals, results in the expression of three LIF transcripts (LIF-D, LIF-M, and LIF-T) differentially expressed from alternate promoters. The first exon of the LIF-T transcript contained no in-frame AUG, causing translation to initiate downstream of the secretory signal sequence at the first AUG in exon two, producing a truncated LIF protein that was localized within the cell. Enforced secretion of this protein demonstrated that it could act as a LIF receptor agonist. Regulated expression of biologically active intracellular and extracellular LIF cytokine could thus provide alternate mechanisms for the modulation of hematopoiesis and immune system function.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.162.8.4637
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1999
    detail.hit.zdb_id: 1475085-5
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  • 7
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    Online Resource
    Human Germ Cell Tumor Cell Lines Express Novel Leukemia Inhibitory Factor Transcripts Encoding Differentially Localized Proteins
    Elsevier BV ; 1999
    In:  Experimental Cell Research Vol. 249, No. 2 ( 1999-06), p. 199-211
    Details
    In: Experimental Cell Research, Elsevier BV, Vol. 249, No. 2 ( 1999-06), p. 199-211
    Type of Medium: Online Resource
    ISSN: 0014-4827
    URL: Article
    DOI: 10.1006/excr.1999.4469
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1999
    detail.hit.zdb_id: 1466780-0
    SSG: 12
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  • 8
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    Online Resource
    Cutting Edge: Influence of the TCR Vβ Domain on the Avidity of CD1d:α-Galactosylceramide Binding by Invariant Vα14 NKT Cells
    The American Association of Immunologists ; 2003
    In:  The Journal of Immunology Vol. 170, No. 12 ( 2003-06-15), p. 5815-5819
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 170, No. 12 ( 2003-06-15), p. 5815-5819
    Abstract: CD1d tetramers loaded with α-galactosylceramide (α-GalCer) bind selectively to mouse invariant Vα14 (Vα14i) NKT cells and their human counterparts. Whereas tetramer binding strictly depends on the expression of a Vα14-Jα18 chain in murine NKT cells, the associated β-chain (typically expressing Vβ8.2 or Vβ7) appears not to influence tetramer binding. In this study, we describe novel α-GalCer-loaded mouse and human CD1d-IgG1 dimers, which revealed an unexpected influence of the TCR-β chain on the avidity of CD1d:α-GalCer binding. A subset of Vα14i NKT cells clearly discriminated α-GalCer bound to mouse or human CD1d on the basis of avidity differences conferred by the Vβ domain of the TCR-β chain, with Vβ8.2 conferring higher avidity binding than Vβ7.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.170.12.5815
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2003
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Online Resource
    REGULATED EXPRESSION OF ALTERNATE TRANSCRIPTS FROM THE MOUSE ONCOSTATIN M GENE: IMPLICATIONS FOR INTERLEUKIN-6 FAMILY CYTOKINES
    Elsevier BV ; 2000
    In:  Cytokine Vol. 12, No. 2 ( 2000-02), p. 134-141
    Details
    In: Cytokine, Elsevier BV, Vol. 12, No. 2 ( 2000-02), p. 134-141
    Type of Medium: Online Resource
    ISSN: 1043-4666
    URL: Article
    DOI: 10.1006/cyto.1999.0541
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2000
    detail.hit.zdb_id: 1463198-2
    SSG: 12
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