Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/17387
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dc.contributor.authorLopez, Jamie A-
dc.contributor.authorNoori, Tahereh-
dc.contributor.authorMinson, Adrian-
dc.contributor.authorLi Jovanoska, Lu-
dc.contributor.authorThia, Kevin-
dc.contributor.authorHildebrand, Michael S-
dc.contributor.authorAkhlaghi, Hedieh-
dc.contributor.authorDarcy, Phillip K-
dc.contributor.authorKershaw, Michael H-
dc.contributor.authorBrown, Natasha J-
dc.contributor.authorGrigg, Andrew P-
dc.contributor.authorTrapani, Joseph A-
dc.contributor.authorVoskoboinik, Ilia-
dc.date2018-03-15-
dc.date.accessioned2018-04-05T02:26:47Z-
dc.date.available2018-04-05T02:26:47Z-
dc.date.issued2018-
dc.identifier.citationFrontiers in immunology 2018; 9: 529-
dc.identifier.issn1664-3224-
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/17387-
dc.description.abstractThe ability of cytotoxic lymphocytes (CL) to eliminate virus-infected or cancerous target cells through the granule exocytosis death pathway is critical to immune homeostasis. Congenital loss of CL function due to bi-allelic mutations inPRF1, UNC13D, STX11, orSTXBP2leads to a potentially fatal immune dysregulation, familial haemophagocytic lymphohistiocytosis (FHL). This occurs due to the failure of CLs to release functional pore-forming protein perforin and, therefore, inability to kill the target cell. Bi-allelic mutations in partner proteinsSTXBP2orSTX11impair CL cytotoxicity due to failed docking/fusion of cytotoxic secretory granules with the plasma membrane. One unique feature of STXBP2- and STX11-deficient patient CLs is that their short-termin vitrotreatment with a low concentration of IL-2 partially or completely restores natural killer (NK) cell degranulation and cytotoxicity, suggesting the existence of a secondary, yet unknown, pathway for secretory granule exocytosis. In the current report, we studied NK and T-cell function in an individual with late presentation of FHL due to hypomorphic bi-allelic mutations inSTXBP2. Intriguingly, in addition to the expected alterations in the STXBP2 and STX11 proteins, we also observed a concomitant significant reduction in the expression of homologous STXBP1 protein and its partner STX1, which had never been implicated in CL function. Further analysis of human NK and T cells demonstrated a functional role for the STXBP1/STX1 axis in NK and CD8+ T-cell cytotoxicity, where it appears to be responsible for as much as 50% of their cytotoxic activity. This discovery suggests a unique and previously unappreciated interplay between STXBP/Munc proteins regulating the same essential granule exocytosis pathway.-
dc.language.isoeng-
dc.subjectMunc18-1-
dc.subjectMunc18-2-
dc.subjectapoptosis-
dc.subjectcytotoxic T cells-
dc.subjectcytotoxic lymphocytes-
dc.subjectfamilial haemophagocytic lymphohistiocytosis-
dc.subjectimmunodeficiency-
dc.subjectnatural killer cells-
dc.titleBi-Allelic Mutations in STXBP2 Reveal a Complementary Role for STXBP1 in Cytotoxic Lymphocyte Killing.-
dc.typeJournal Article-
dc.identifier.journaltitleFrontiers in immunology-
dc.identifier.affiliationCancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia-
dc.identifier.affiliationSir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia-
dc.identifier.affiliationDepartment of Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia-
dc.identifier.affiliationDepartment of Medicine, Austin Health, Heidelberg, Victoria, Australia-
dc.identifier.affiliationDepartment of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia-
dc.identifier.doi10.3389/fimmu.2018.00529-
dc.identifier.orcid0000-0003-2739-0515-
dc.identifier.pubmedid29599780-
dc.type.austinJournal Article-
local.name.researcherHildebrand, Michael S
item.openairetypeJournal Article-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextnone-
item.fulltextNo Fulltext-
item.cerifentitytypePublications-
item.languageiso639-1en-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptMedicine (University of Melbourne)-
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