Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes.
Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8+ T cells. We report that CD8+ T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8+ T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8+ T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8+ T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8+ T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.
Herz
Jasmin
J
Institute for Medical Microbiology, Immunology and Hygiene, Medical Center, University of Cologne, Germany.
Pardo
Julian
J
Kashkar
Hamid
H
Schramm
Michael
M
Kuzmenkina
Elza
E
Bos
Erik
E
Wiegmann
Katja
K
Wallich
Reinhard
R
Peters
Peter J
PJ
Herzig
Stefan
S
Schmelzer
Elmon
E
Krönke
Martin
M
Simon
Markus M
MM
Utermöhlen
Olaf
O
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D054992:Immunological Synapses / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022142:Secretory Vesicles / Q000201:enzymology / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D018946:Chemokine CCL5; D054353:Perforin; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D053804:Granzymes