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

2022 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Chang, Hsin-Fang, Schirra, C., Ninov, M., Hahn, U., Ravichandran, K., Krause, E., Becherer, U. ... Rettig, J. (2022). ​Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes. Nature Communications13(1), Article 1029​. ​doi: https://doi.org/10.1038/s41467-022-28596-y 

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Authors
Chang, Hsin-Fang; Schirra, Claudia; Ninov, Momchil; Hahn, Ulrike; Ravichandran, Keerthana; Krause, Elmar; Becherer, Ute; Bálint, Štefan; Harkiolaki, Maria; Urlaub, Henning ; Rettig, Jens
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.
Issue Date
2022
Journal
Nature Communications 
Project
SFB 1286: Quantitative Synaptologie 
SFB 1286 | A08: Die Rolle post-translational modifizierter Proteine in der synaptischen Übertragung 
SFB 1286 | A06: Mitochondrienfunktion und -umsatz in Synapsen 
Working Group
RG R. Jahn (Laboratory of Neurobiology) 
RG Urlaub (Bioanalytische Massenspektrometrie) 
External URL
https://sfb1286.uni-goettingen.de/literature/publications/156
eISSN
2041-1723
Language
English

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