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.
Highlights
Chediak–Higashi syndrome (CHS, MIM 214500) is an autosomal recessive disease associated with mutations in LYST [1,2,3]
In characterizing this cohort of CHS patients, we identified biallelic mutations in LYST in a total of 21 patients from 14 unrelated families (Table 1)
With the exception of LYST p.A1454N and p.G408R, which were present in compound heterozygous form, all mutations were nonsense or frameshift mutations predicted to result in truncated LYST protein
Summary
Chediak–Higashi syndrome (CHS, MIM 214500) is an autosomal recessive disease associated with mutations in LYST [1,2,3]. The defining characteristic of CHS is giant lysosomes and lysosome-related organelles [12] While this does not seem to impair the physiology of most cell types [12], functional defects are apparent in cells that perform lysosomal secretion, including melanocytes, lymphocytes, platelets, MHC class II-expressing antigen presenting cells, and glial cells, resulting in oculocutaneous albinism and prolonged bleeding [13]. A study encompassing analyses of mouse models as well as human CHS patients indicated that the risk of HLH development in CHS is determined by subtle differences in cytotoxic T lymphocyte (CTL) function, while NK cell cytotoxic function was generally more severely and uniformly compromised [20]. Statistical analysis was performed using Prism software (version 5, GraphPad Software, Inc.), as specified
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