Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak-Higashi Syndrome Patients
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Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak-Higashi Syndrome Patients. / 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.
In: FRONT IMMUNOL, Vol. 8, 2017, p. 426.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Differences in Granule Morphology yet Equally Impaired Exocytosis among Cytotoxic T Cells and NK Cells from Chediak-Higashi Syndrome Patients
AU - Chiang, Samuel C C
AU - Wood, Stephanie M
AU - Tesi, Bianca
AU - Akar, Himmet Haluk
AU - Al-Herz, Waleed
AU - Ammann, Sandra
AU - Belen, Fatma Burcu
AU - Caliskan, Umran
AU - Kaya, Zühre
AU - Lehmberg, Kai
AU - Patiroglu, Turkan
AU - Tokgoz, Huseyin
AU - Ünüvar, Ayşegül
AU - Introne, Wendy J
AU - Henter, Jan-Inge
AU - Nordenskjöld, Magnus
AU - Ljunggren, Hans-Gustaf
AU - Meeths, Marie
AU - Ehl, Stephan
AU - Krzewski, Konrad
AU - Bryceson, Yenan T
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.3389/fimmu.2017.00426
DO - 10.3389/fimmu.2017.00426
M3 - SCORING: Journal article
C2 - 28458669
VL - 8
SP - 426
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
ER -
