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

Author

Listed:
  • Hsin-Fang Chang

    (Saarland University)

  • Claudia Schirra

    (Saarland University)

  • Momchil Ninov

    (Max Planck Institute for Multidisciplinary Sciences
    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)

  • Štefan Bálint

    (University of Oxford)

  • Maria Harkiolaki

    (Harwell Science and Innovation Campus)

  • 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)

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.

Suggested Citation

  • Hsin-Fang Chang & Claudia Schirra & Momchil Ninov & Ulrike Hahn & Keerthana Ravichandran & Elmar Krause & Ute Becherer & Štefan Bálint & Maria Harkiolaki & Henning Urlaub & Salvatore Valitutti & Cosim, 2022. "Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28596-y
    DOI: 10.1038/s41467-022-28596-y
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    References listed on IDEAS

    as
    1. Wenyan Fu & Changhai Lei & Shuowu Liu & Yingshu Cui & Chuqi Wang & Kewen Qian & Tian Li & Yafeng Shen & Xiaoyan Fan & Fangxing Lin & Min Ding & Mingzhu Pan & Xuting Ye & Yongji Yang & Shi Hu, 2019. "CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Ulf Matti & Varsha Pattu & Mahantappa Halimani & Claudia Schirra & Elmar Krause & Yuanyuan Liu & Lisa Weins & Hsin Fang Chang & Raul Guzman & Jenny Olausson & Marc Freichel & Frank Schmitz & Mathias P, 2013. "Synaptobrevin2 is the v-SNARE required for cytotoxic T-lymphocyte lytic granule fusion," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
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    1. Kévin Cortacero & Brienne McKenzie & Sabina Müller & Roxana Khazen & Fanny Lafouresse & Gaëlle Corsaut & Nathalie Acker & François-Xavier Frenois & Laurence Lamant & Nicolas Meyer & Béatrice Vergier &, 2023. "Evolutionary design of explainable algorithms for biomedical image segmentation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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