Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes

Jasmin Herz, Julian Pardo, Hamid Kashkar, Michael Schramm, Elza Kuzmenkina, Erik Bos, Katja Wiegmann, Reinhard Wallich, Peter J. Peters, Stefan Herzig, Elmon Schmelzer, Martin Krönke, Markus M. Simon, Olaf Utermöhlen

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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.

Original languageEnglish
Pages (from-to)761-768
Number of pages8
JournalNature immunology
Volume10
Issue number7
DOIs
StatePublished - 2009

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