Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 8, Pages 3324-3329Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1013285108
Keywords
primary immunodeficiency; cytotoxic lymphocytes; lytic granules; perforin
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Funding
- Bundesministerium fur Bildung und Forschung [01 EO 0803]
- Deutsche Forschungsgemeinschaft [SFB620 TP A4, SFB620 TP B6]
- Swedish Research Council
- Society for Medical Research
- Mary Beve's Foundation
- Clas Groschinsky's Memorial Fund
- Shizu Matsumaras Donation
- Karolinska Institute Research Foundation
- National Institutes of Health [AI066128]
- Grants-in-Aid for Scientific Research [20220007] Funding Source: KAKEN
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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-1 beta and the cytokines TNF-alpha and IFN-gamma 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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