AUTHOR=Chiang Samuel C. C. , Wood Stephanie M. , Tesi Bianca , Akar Himmet Haluk , Al-Herz Waleed , Ammann Sandra , Belen Fatma Burcu , Caliskan Umran , Kaya Zühre , Lehmberg Kai , Patiroglu Turkan , Tokgoz Huseyin , Ünüvar Ayşegül , Introne Wendy J. , Henter Jan-Inge , Nordenskjöld Magnus , Ljunggren Hans-Gustaf , Meeths Marie , Ehl Stephan , Krzewski Konrad , Bryceson Yenan T. TITLE=Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak–Higashi Syndrome Patients JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2017 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00426 DOI=10.3389/fimmu.2017.00426 ISSN=1664-3224 ABSTRACT=

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 cell- and 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.