title: Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes.
abstract: 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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Medical Center, University of Cologne, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Herz
authors.forename: Julian
authors.initials: J
authors.lastname: Pardo
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.forename: Michael
authors.initials: M
authors.lastname: Schramm
authors.forename: Elza
authors.initials: E
authors.lastname: Kuzmenkina
authors.forename: Erik
authors.initials: E
authors.lastname: Bos
authors.forename: Katja
authors.initials: K
authors.lastname: Wiegmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Peters
authors.forename: Stefan
authors.initials: S
authors.lastname: Herzig
authors.forename: Elmon
authors.initials: E
authors.lastname: Schmelzer
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
mesh_terms: 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
chemical_list: D018946:Chemokine CCL5; D054353:Perforin; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D053804:Granzymes