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

• DOI: 10.1038/ni1000
• Publication Date: 2003-10-19T18:27:52Z
• Authors: Richard H Clark; Jane C Stinchcombe; Anna Day; Emma Blott; Sarah Booth; Giovanna Bossi; Terry Hamblin; E Graham Davies; Gillian M Griffiths
• Keywords: 0301 basic medicine; Base Sequence; Adaptor Protein Complex 3; Tetraspanin 30; Molecular Sequence Data; 610; Membrane Transport Proteins; Proteins; 612; Platelet Membrane Glycoproteins; Cytoplasmic Granules; Microtubules; 3. Good health; 03 medical and health sciences; Antigens, CD; Hermanski-Pudlak Syndrome; Immune System; Mutation; Humans; Adaptor Protein Complex beta Subunits; T-Lymphocytes, Cytotoxic

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.