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

Nat Immunol. 2007 Mar;8(3):257-67. doi: 10.1038/ni1431. Epub 2007 Jan 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Polarity
  • Cells, Cultured
  • Cytotoxicity, Immunologic / physiology*
  • Endosomes / immunology
  • Endosomes / metabolism
  • Endosomes / ultrastructure
  • Exocytosis / immunology*
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / ultrastructure
  • Lymphocyte Activation / immunology
  • Lysosomes / immunology
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • Microscopy, Electron, Transmission
  • Microscopy, Immunoelectron
  • Nerve Tissue Proteins / immunology*
  • Nerve Tissue Proteins / metabolism
  • Polymerase Chain Reaction
  • Secretory Vesicles / immunology*
  • Secretory Vesicles / metabolism
  • Secretory Vesicles / ultrastructure
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Cytotoxic / ultrastructure
  • Transfection
  • rab GTP-Binding Proteins / immunology
  • rab GTP-Binding Proteins / metabolism
  • rab27 GTP-Binding Proteins


  • Nerve Tissue Proteins
  • UNC13B protein, human
  • rab27 GTP-Binding Proteins
  • RAB27A protein, human
  • rab GTP-Binding Proteins