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

Hsin-Fang Chang (), Claudia Schirra, Momchil Ninov, Ulrike Hahn, Keerthana Ravichandran, Elmar Krause, Ute Becherer, Štefan Bálint, Maria Harkiolaki, Henning Urlaub, Salvatore Valitutti, Cosima T. Baldari, Michael L. Dustin, Reinhard Jahn and Jens Rettig ()
Additional contact information
Hsin-Fang Chang: Saarland University
Claudia Schirra: Saarland University
Momchil Ninov: Max Planck Institute for Multidisciplinary Sciences
Ulrike Hahn: Saarland University
Keerthana Ravichandran: Saarland University
Elmar Krause: Saarland University
Ute Becherer: Saarland University
Štefan Bálint: University of Oxford
Maria Harkiolaki: Harwell Science and Innovation Campus
Henning Urlaub: Max Planck Institute for Multidisciplinary Sciences
Salvatore Valitutti: Cancer Research Center of Toulouse, INSERM U1037
Cosima T. Baldari: University of Siena
Michael L. Dustin: University of Oxford
Reinhard Jahn: Max Planck Institute for Multidisciplinary Sciences
Jens Rettig: Saarland University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28596-y

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