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

Andrea Maul-Pavicic, Samuel C. C. Chiang, Anne Rensing-Ehl, Birthe Jessen, Cyril Fauriat, Stephanie M. Wood, Sebastian Sjöqvist, Markus Hufnagel, Ilka Schulze, Thilo Bass, Wolfgang W. Schamel, Sebastian Fuchs, Hanspeter Pircher, Christie-Ann McCarl, Katsuhiko Mikoshiba, Klaus Schwarz, Stefan Feske, Yenan T. Bryceson, Stephan Ehl and Wayne M. Yokoyama
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 8 (February 22, 2011), pp. 3324-3329
Stable URL: http://www.jstor.org/stable/41060926
Page Count: 6
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ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis
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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 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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