ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis |
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Authors: | Maul-Pavicic Andrea Chiang Samuel C C Rensing-Ehl Anne Jessen Birthe Fauriat Cyril Wood Stephanie M Sjöqvist Sebastian Hufnagel Markus Schulze Ilka Bass Thilo Schamel Wolfgang W Fuchs Sebastian Pircher Hanspeter McCarl Christie-Ann Mikoshiba Katsuhiko Schwarz Klaus Feske Stefan Bryceson Yenan T Ehl Stephan |
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Affiliation: | Centre of Chronic Immunodeficiency and Centre for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany. |
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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 Ca(2+) 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 Ca(2+) influx in granule exocytosis for lymphocyte cytotoxicity as well as for cytokine production induced by target cell recognition. |
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Keywords: | primary immunodeficiency cytotoxic lymphocytes lytic granules perforin |
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