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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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 Creators:
Maul-Pavicic, Andrea1, Author              
Chiang, Samuel C. C., Author
Rensing-Ehl, Anne, Author
Jessen, Birthe, Author
Fauriate, Cyril, Author
Wood, Stephanie M., Author
Sjöqvist, Sebastian, Author
Hufnagel, Markus, Author
Schulze, Ilka, Author
Bass, Thilo1, Author              
Schamel, Wolfgang W.1, Author              
Fuchs, Sebastian, Author
Pircher, Hans-Peter, Author
McCarl, Christie-Ann, Author
Mikoshiba, Katsuhiko, Author
Schwarz, Klaus2, Author              
Feske, Stefan, Author
Bryceson, Yenan T., Author
Ehl, Stephan, Author
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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Free keywords: primary immunodeficiency; cytotoxic lymphocytes; lytic granules; perforin
 Abstract: 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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Language(s): eng - English
 Dates: 2011-02-22
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 577776
 Degree: -

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Title: Proceedings of the National Academy of Sciences U.S.A.
  Alternative Title : PNAS
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 108 Sequence Number: - Start / End Page: 3324 - 3329 Identifier: -