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

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Chiang S. C. C., Wood S. M., Tesi B., Akar H. H., Al-Herz W., Ammann S., ...More

Frontiers in immunology, vol.8, pp.426, 2017 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 8
  • Publication Date: 2017
  • Doi Number: 10.3389/fimmu.2017.00426
  • Journal Name: Frontiers in immunology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.426
  • Keywords: Chediak-Higashi syndrome, NK cells, cytotoxic T cells, exocytosis, lytic granule polarization, lysosomes, endosomes, HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, CLINICAL PRESENTATIONS, MUTATIONS, PROTEIN, GENE, IDENTIFICATION, DEGRANULATION, BIOGENESIS, SPECTRUM, POLARIZATION
  • Gazi University Affiliated: Yes


Chediak-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.