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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 06 December 2013, Vol.342(6163), pp.1247-50
    Description: The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.
    Keywords: Cytotoxicity, Immunologic ; Immunological Synapses ; Signal Transduction ; Cd8-Positive T-Lymphocytes -- Immunology ; Hedgehog Proteins -- Metabolism ; T-Lymphocytes, Cytotoxic -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Oct 2, 2018, Vol.115(40), p.E9353(9)
    Description: The repertoire of peptides displayed at the cell surface by MHC I molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both of these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyzes peptide exchange on surface-expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the luminal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFN-[gamma] secretion, and T cell-mediated killing of target cells. Thus, we have developed an efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumors in the future. TAPBPR/TAPBPL | MHC | HLA | antigen processing | antigen presentation
    Keywords: HLA ; Mhc ; Tapbpr/Tapbpl ; Antigen Presentation ; Antigen Processing ; Antigen Presentation ; Histocompatibility Antigens Class I -- Immunology ; Immunoglobulins -- Immunology ; Membrane Proteins -- Immunology ; Peptides -- Immunology;
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 August 2012, Vol.109(33), pp.E2223-9
    Description: During the primary response, the commitment of the CD8(+) T cell to Blimp-1 expression and the terminal differentiation that Blimp-1 induces must be timed so as not to impair the process of clonal expansion. We determined whether the Hippo pathway, which links cell-cell contact to differentiation in other cell lineages, controls Blimp-1 expression. Activating the CD8(+) T cell with antigen and IL-2 causes expression of the core Hippo pathway components, including the pivotal transcriptional cofactor Yap. Contact between activated CD8(+) T cells induces Hippo pathway-mediated Yap degradation and Blimp-1 expression; a Hippo-resistant, stable form of Yap suppresses Blimp-1 expression. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and CD80 comprise the receptor-ligand pair that mediates contact-dependent Hippo pathway activation. In vivo, CD8(+) T cells expressing Hippo resistant-Yap or lacking CTLA-4 have diminished expression of the senescence marker, KLRG1, during a viral infection. The CTLA-4/Hippo pathway/Blimp-1 system may couple terminal differentiation of CD8(+) T cell with the magnitude of clonal expansion.
    Keywords: Cd8-Positive T-Lymphocytes -- Enzymology ; Ctla-4 Antigen -- Metabolism ; Lymphocyte Activation -- Immunology ; Protein-Serine-Threonine Kinases -- Metabolism ; Signal Transduction -- Immunology ; Transcription Factors -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Description: The repertoire of peptides displayed at the cell surface by major histocompatibility complex class I (MHC I) molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyses peptide exchange on surface expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the lumenal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two novel systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFNγ secretion, and T cell-mediated killing of target cells. Thus, we have developed a novel and efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto...
    Keywords: T-Lymphocytes ; Hela Cells ; Animals ; Mice, Knockout ; Humans ; Mice ; Peptides ; Immunoglobulins ; Membrane Proteins ; Receptors, Antigen, T-Cell ; Histocompatibility Antigens Class I ; Immunity, Cellular ; Antigen Presentation ; Interferon-Gamma ; Mcf-7 Cells
    ISSN: 0027-8424
    Source: DataCite
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  • 5
    Language: English
    In: The Journal of cell biology, 21 February 2011, Vol.192(4), pp.663-74
    Description: Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor-activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane.
    Keywords: Cell Membrane -- Metabolism ; Centrosome -- Metabolism ; Immunological Synapses -- Metabolism ; Lymphocyte Specific Protein Tyrosine Kinase P56(Lck) -- Physiology ; T-Lymphocytes, Cytotoxic -- Enzymology
    ISSN: 00219525
    E-ISSN: 1540-8140
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  • 6
    Language: English
    In: Science (New York, N.Y.), 31 March 2017, Vol.355(6332), pp.1433-1436
    Description: Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4 T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.
    Keywords: Transcriptome ; Aging -- Genetics ; Cd4-Positive T-Lymphocytes -- Immunology ; Immunologic Memory -- Genetics
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 7
    Language: English
    Description: Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4(+) T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues....
    ISSN: 0036-8075
    Source: DataCite
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  • 8
    In: Nature Reviews Immunology, 2016
    Description: Cytotoxic T lymphocytes (CTLs) kill virus-infected and tumour cells with remarkable specificity. Upon recognition, CTLs form a cytolytic immune synapse with their target cell, and marked reorganization of both the actin and the microtubule cytoskeletons brings the centrosome up to the plasma membrane to the point of T cell receptor signalling. Secretory granules move towards the centrosome and are delivered to this focal point of secretion. Such centrosomal docking at the plasma membrane also occurs during ciliogenesis; indeed, striking similarities exist between the cytolytic synapse and the primary cilium that throw light on the possible origins of immune synapses.
    Keywords: Antigens – Health Aspects ; Antigens – Research ; Muscle Proteins – Physiological Aspects ; Muscle Proteins – Research ; Synapses – Physiological Aspects ; Synapses – Research;
    ISSN: 1474-1733
    E-ISSN: 14741741
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  • 9
    Language: English
    Description: Cytotoxic T lymphocytes (CTLs) kill virus-infected and tumour cells with remarkable specificity. Upon recognition, CTLs form a cytolytic immune synapse with their target cell and marked reorganization of both the actin and microtubule cytoskeletons brings the centrosome right up to the plasma membrane to the point of T cell receptor (TCR) signalling. Secretory granules move towards the centrosome and are delivered to this focal point of secretion. Such centrosomal docking at the plasma membrane also occurs during ciliogenesis; indeed, striking similarities exist between the cytolytic synapse and primary cilium that throw light on the possible origins of immune synapses.
    Description: GMG is funded by Wellcome Trust Principal Research Fellowship [103930], MDR is now funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society [107609].
    Description: This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group.
    Source: DSpace@Cambridge
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  • 10
    Language: English
    Description: The repertoire of peptides displayed at the cell surface by major histocompatibility complex class I (MHC I) molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyses peptide exchange on surface expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the lumenal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two novel systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFNγ secretion, and T cell-mediated killing of target cells. Thus, we have developed a novel and efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumours in the future.
    Keywords: T-Lymphocytes ; Hela Cells ; Animals ; Mice, Knockout ; Humans ; Mice ; Peptides ; Immunoglobulins ; Membrane Proteins ; Receptors, Antigen, T-Cell ; Histocompatibility Antigens Class I ; Immunity, Cellular ; Antigen Presentation ; Interferon-Gamma ; Mcf-7 Cells
    Source: DSpace@Cambridge
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