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

Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3324-9. doi: 10.1073/pnas.1013285108. Epub 2011 Feb 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / immunology*
  • Calcium Channels / immunology*
  • Cell Degranulation / immunology*
  • Chemokine CCL4 / biosynthesis
  • Cytokines / biosynthesis*
  • Cytotoxicity, Immunologic*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukins / biosynthesis
  • Killer Cells, Natural / pathology
  • ORAI1 Protein
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Calcium Channels
  • Chemokine CCL4
  • Cytokines
  • Interleukins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Calcium