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

DOI: 10.1038/s41467-022-28596-y DOI Help

Authors: Hsin-Fang Chang (Saarland University) , Claudia Schirra (Saarland University) , Momchil Ninov (Max Planck Institute for Multidisciplinary Sciences; University Medical Center Göttingen) , Ulrike Hahn (Saarland University) , Keerthana Ravichandran (Saarland University) , Elmar Krause (Saarland University) , Ute Becherer (Saarland University) , Stefan Balint (University of Oxford) , Maria Harkiolaki (Diamond Light Source) , Henning Urlaub (Max Planck Institute for Multidisciplinary Sciences; University Medical Center Göttingen) , Salvatore Valitutti (Cancer Research Center of Toulouse, INSERM U1037; Institut Universitaire du Cancer-Oncopole de Toulouse) , Cosima T. Baldari (University of Siena) , Michael L. Dustin (University of Oxford) , Reinhard Jahn (Max Planck Institute for Multidisciplinary Sciences) , Jens Rettig (Saarland University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 13

State: Published (Approved)
Published: February 2022

Open Access Open Access

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.

Journal Keywords: Cytotoxic T cells; Imaging the immune system; Lysosomes

Subject Areas: Biology and Bio-materials

Instruments: B24-Cryo Soft X-ray Tomography

Added On: 28/02/2022 13:19


Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Imaging Tomography Cryo-soft X-ray Tomography (Cryo-SXT)