Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak-Higashi Syndrome Patients

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dc.contributor.authorChiang, Samuel C. C.
dc.contributor.authorWood, Stephanie M.
dc.contributor.authorTesi, Bianca
dc.contributor.authorAkar, Himmet Haluk
dc.contributor.authorAl-Herz, Waleed
dc.contributor.authorAmmann, Sandra
dc.contributor.authorBelen, Fatma Burcu
dc.date.accessioned2024-02-23T14:34:56Z
dc.date.available2024-02-23T14:34:56Z
dc.date.issued2017
dc.departmentNEÜen_US
dc.description.abstractChediak-Higashi syndrome (CHS) is caused by autosomal recessive mutations in LYST, resulting in enlarged lysosomal compartments in multiple cell types. CHS patients display oculocutaneous albinism and may develop life-threatening hemophagocytic lymphohistiocytosis (HLH). While NK cell-mediated cytotoxicity has been reported to be uniformly defective, variable defects in T cell-mediated cytotoxicity has been observed. The latter has been linked to the degree of HLH susceptibility. Since the discrepancies in NK celland T cell-mediated cellular cytotoxicity might result from differences in regulation of cytotoxic granule release, we here evaluated perforin-containing secretory lysosome size and number in freshly isolated lymphocytes from CHS patients and furthermore compared their exocytic capacities. Whereas NK cells from CHS patients generally contained a single, gigantic perforin-containing granule, cytotoxic T cells predominantly contained several smaller granules. Nonetheless, in a cohort of 21 CHS patients, cytotoxic T cell and NK cell granule exocytosis were similarly impaired upon activating receptor stimulation. Mechanistically, polarization of cytotoxic granules was defective in cytotoxic lymphocytes from CHS patients, with EEA1, a marker of early endosomes, mislocalizing to lysosomal structures. The results leads to the conclusion that lysosome enlargement corresponds to loss of distinct organelle identity in the endocytic pathway, which on a subcellular level more adversely affects NK cells than T cells. Hence, vesicular size or numbers do not per se dictate the impairment of lysosomal exocytosis in the two cell types studied.en_US
dc.description.sponsorshipEuropean Research Council under the European Union's Seventh Framework Programme (FP)/ERC Grant [311335]; Swedish Research Council; Norwegian Research Council; Swedish Foundation for Strategic Research; Wallenberg Foundation; Swedish Cancer Foundation; Swedish Childhood Cancer Foundation; Stockholm County Council; Karolinska Institutet Center for Innovative Medicine; BMBF [BMBF 01 EO 0803]; DFG [SFB1160, TP1]en_US
dc.description.sponsorshipThis study was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 311335, Swedish Research Council, Norwegian Research Council, Swedish Foundation for Strategic Research, Wallenberg Foundation, Swedish Cancer Foundation, Swedish Childhood Cancer Foundation, as well as the Stockholm County Council and Karolinska Institutet Center for Innovative Medicine (to YB); by the Swedish Research Council, Swedish Cancer Foundation, Swedish Childhood Cancer Foundation, and the Stockholm County Council (to J-IH); and by the BMBF (BMBF 01 EO 0803) and the DFG (SFB1160, TP1) (to SE).en_US
dc.identifier.doi10.3389/fimmu.2017.00426
dc.identifier.issn1664-3224
dc.identifier.pmid28458669en_US
dc.identifier.scopus2-s2.0-85018404634en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3389/fimmu.2017.00426
dc.identifier.urihttps://hdl.handle.net/20.500.12452/15822
dc.identifier.volume8en_US
dc.identifier.wosWOS:000399425000002en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherFrontiers Media Saen_US
dc.relation.ispartofFrontiers In Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectChediak-Higashi Syndromeen_US
dc.subjectNk Cellsen_US
dc.subjectCytotoxic T Cellsen_US
dc.subjectExocytosisen_US
dc.subjectLytic Granule Polarizationen_US
dc.subjectLysosomesen_US
dc.subjectEndosomesen_US
dc.titleDifferences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak-Higashi Syndrome Patientsen_US
dc.typeArticleen_US

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