title: ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis.
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.
authors.affiliation: Centre of Chronic Immunodeficiency and Centre for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Maul-Pavicic
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.forename: Birthe
authors.initials: B
authors.lastname: Jessen
authors.forename: Cyril
authors.initials: C
authors.lastname: Fauriat
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Wood
authors.forename: Sebastian
authors.initials: S
authors.lastname: Sjöqvist
authors.forename: Markus
authors.initials: M
authors.lastname: Hufnagel
authors.forename: Ilka
authors.initials: I
authors.lastname: Schulze
authors.forename: Thilo
authors.initials: T
authors.lastname: Bass
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Schamel
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.forename: Christie-Ann
authors.initials: CA
authors.lastname: McCarl
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D002118:Calcium / Q000276:immunology*; D015220:Calcium Channels / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology*; D054407:Chemokine CCL4 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000473:pathology; D000071740:ORAI1 Protein; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015220:Calcium Channels; D054407:Chemokine CCL4; D016207:Cytokines; D007378:Interleukins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002118:Calcium