Nature Immunology4, 1111 - 1120 (2003)
Published online: 19 October 2003; | doi:10.1038/ni1000
Adaptor protein 3−dependent microtubule-mediated movement of lytic granules to the immunological synapse
Richard H Clark1, 4, Jane C Stinchcombe1, 4, Anna Day1, Emma Blott1, Sarah Booth1, Giovanna Bossi1, Terry Hamblin2, E Graham Davies3
& Gillian M Griffiths1
1
Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.
2
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, BH7 7DW, UK.
3
Great Ormond Street Hospital for Children, London WC1N 3GH, UK.
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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