Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 02 2022
24 02 2022
Historique:
received:
04
05
2021
accepted:
24
01
2022
entrez:
25
2
2022
pubmed:
26
2
2022
medline:
13
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35210420
doi: 10.1038/s41467-022-28596-y
pii: 10.1038/s41467-022-28596-y
pmc: PMC8873490
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1029Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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