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

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Pardo,  Julian
Metchnikoff Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Simon,  Markus M.
Metchnikoff Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Herz, J., Pardo, J., Kashkar, H., Schramm, M., Kuzmenkina, E., Bos, E., et al. (2009). Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nature Immunology, 10, 761-768.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-8F6B-2
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.