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Journal Article

Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes

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Ninov,  M.
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Urlaub,  H.
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Jahn,  R.
Emeritus Group Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Chang, H.-F., Schirra, C., Ninov, M., Hahn, U., Ravichandran, K., Krause, E., et al. (2022). Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes. Nature Communications, 13: 1029. doi:10.1038/s41467-022-28596-y.


Cite as: https://hdl.handle.net/21.11116/0000-000A-90FD-6
Abstract
Cytotoxic T lymphocytes (CTL) kill malignant and infected cells through the directed release
of cytotoxic proteins into the immunological synapse (IS). The cytotoxic protein granzyme B
(GzmB) is released in its soluble form or in supramolecular attack particles (SMAP). We
utilize synaptobrevin2-mRFP knock-in mice to isolate fusogenic cytotoxic granules in an
unbiased manner and visualize them alone or in degranulating CTLs. We identified two
classes of fusion-competent granules, single core granules (SCG) and multi core granules
(MCG), with different diameter, morphology and protein composition. Functional analyses
demonstrate that both classes of granules fuse with the plasma membrane at the IS. SCG
fusion releases soluble GzmB. MCGs can be labelled with the SMAP marker
thrombospondin-1 and their fusion releases intact SMAPs. We propose that CTLs use SCG
fusion to fill the synaptic cleft with active cytotoxic proteins instantly and parallel MCG fusion
to deliver latent SMAPs for delayed killing of refractory targets.