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  ORAI1-mediated calcium influx is requried for human cytotoxic lymphocyte degranulation and target cell lysis

Maul-Pavicic, A., Chiang, S. C. C., Rensing-Ehl, A., Jessen, B., Fauriate, C., Wood, S. M., et al. (2011). ORAI1-mediated calcium influx is requried for human cytotoxic lymphocyte degranulation and target cell lysis. Proceedings of the National Academy of Sciences U.S.A., 108, 3324-3329.

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Maul-Pavicic, Andrea1, Autor           
Chiang, Samuel C. C., Autor
Rensing-Ehl, Anne, Autor
Jessen, Birthe, Autor
Fauriate, Cyril, Autor
Wood, Stephanie M., Autor
Sjöqvist, Sebastian, Autor
Hufnagel, Markus, Autor
Schulze, Ilka, Autor
Bass, Thilo1, Autor           
Schamel, Wolfgang W.1, Autor           
Fuchs, Sebastian, Autor
Pircher, Hans-Peter, Autor
McCarl, Christie-Ann, Autor
Mikoshiba, Katsuhiko, Autor
Schwarz, Klaus2, Autor           
Feske, Stefan, Autor
Bryceson, Yenan T., Autor
Ehl, Stephan, Autor
Affiliations:
1Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243645              
2Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              

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Schlagwörter: primary immunodeficiency; cytotoxic lymphocytes; lytic granules; perforin
 Zusammenfassung: Lymphocytes mediate cytotoxicity by polarized release of the contents of cytotoxic granules toward their target cells. Here, we have studied the role of the calcium release-activated calcium channel ORAI1 in human lymphocyte cytotoxicity. Natural killer (NK) cells obtained from an ORAI1-deficient patient displayed defective store-operated Ca2+ entry (SOCE) and severely defective cytotoxic granule exocytosis leading to impaired target cell lysis. Similar findings were obtained using NK cells from a stromal interaction molecule 1-deficient patient. The defect occurred at a late stage of the signaling process, because activation of leukocyte functional antigen (LFA)-1 and cytotoxic granule polarization were not impaired. Moreover, pharmacological inhibition of SOCE interfered with degranulation and target cell lysis by freshly isolated NK cells and CD8+ effector T cells from healthy donors. In addition to effects on lymphocyte cytotoxicity, synthesis of the chemokine macrophage inflammatory protein-1β and the cytokines TNF-α and IFN-γ on target cell recognition was impaired in ORAI1-deficient NK cells, as previously described for T cells. By contrast, NK cell cytokine production induced by combinations of IL-12, IL-15, and IL-18 was not impaired by ORAI1 deficiency. Taken together, these results identify a critical role for ORAI1-mediated Ca2+ influx in granule exocytosis for lymphocyte cytotoxicity as well as for cytokine production induced by target cell recognition.

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Sprache(n): eng - English
 Datum: 2011-02-22
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 577776
 Art des Abschluß: -

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Titel: Proceedings of the National Academy of Sciences U.S.A.
  Alternativer Titel : PNAS
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 108 Artikelnummer: - Start- / Endseite: 3324 - 3329 Identifikator: -