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Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4

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Ménager, Mickaël | Ménasché, Gaël | Romao, Maryse | Knapnougel, Perrine | Ho, Chen-Hsuan | Garfa, Meriem | Raposo, Graça | Feldmann, Jerome | Fischer, Alain | de Saint Basile, Geneviève

Edité par CCSD ; Nature Publishing Group -

International audience. Cytotoxic T lymphocytes and natural killer cells exert their cytotoxic activity through the polarized secretion of cytotoxic granules at the immunological synapse. Rab27a and hMunc13-4 are critical effectors of the exocytosis of cytotoxic granules. Here we show that the cytotoxic function of lymphocytes requires the cooperation of two types of organelles: the lysosomal cytotoxic granule and the endosomal 'exocytic vesicle'. Independently of Rab27a, hMunc13-4 mediated the assembly of Rab11(+) recycling and Rab27(+) late endosomal vesicles, constituting a pool of vesicles destined for regulated exocytosis. It also primed cytotoxic granule fusion, possibly through interaction with active Rab27a. Cytotoxic T lymphocyte-target cell recognition induced rapid polarization of both types of organelles, which coalesced near the cell-cell contact area. Our data provide insight into the regulation of the generation and release of cytotoxic granules by effector cytotoxic T lymphocytes and natural killer cells.

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