Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse

Clark, Richard H., Stinchcombe, Jane C., Day, Anna, Blott, Emma, Booth, Sarah, Bossi, Giovanna, Hamblin, Terry, Davies, E. Graham and Griffiths, Gillian M. (2003) Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nature Immunology, 4 (11), 1111-1120. (doi:10.1038/ni1000).

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. Individuals with HPS type 2 (HPS2) lack the cytosolic adaptor protein 3 (AP-3) involved in lysosomal sorting, and are also immunodeficient. Here we characterize an HPS2 mutation and demonstrate that AP-3 deficiency leads to a loss of cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Although the lysosomal protein CD63 was mislocalized to the plasma membrane, perforin and granzymes were correctly localized to the lytic granules in AP-3-deficient CTLs. However, the lytic granules of AP-3-deficient CTLs were enlarged and were unable to move along microtubules and dock within the secretory domain of the immunological synapse. These data show that AP-3 is essential for polarized secretion from CTLs.

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