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

Granules containing perforin and granzymes are secreted from cytotoxic T lymphocytes. Krönke and co-workers find that acid sphingomyelase is needed for granule shrinkage just before exocytosis in this process. 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.