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Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity

Author

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  • Mitchell S. Wang

    (Immunology Program, Memorial Sloan Kettering Cancer Center
    Pharmacology Program, Weill-Cornell Graduate School of Medical Sciences)

  • Yuesong Hu

    (Emory University)

  • Elisa E. Sanchez

    (Immunology Program, Memorial Sloan Kettering Cancer Center
    Weill-Cornell Graduate School of Medical Sciences)

  • Xihe Xie

    (Neuroscience Program, Weill-Cornell Graduate School of Medical Sciences)

  • Nathan H. Roy

    (State University of New York Upstate Medical University)

  • Miguel Jesus

    (Immunology Program, Memorial Sloan Kettering Cancer Center)

  • Benjamin Y. Winer

    (Immunology Program, Memorial Sloan Kettering Cancer Center)

  • Elizabeth A. Zale

    (Immunology Program, Memorial Sloan Kettering Cancer Center)

  • Weiyang Jin

    (Columbia University)

  • Chirag Sachar

    (Columbia University)

  • Joanne H. Lee

    (Columbia University)

  • Yeonsun Hong

    (University of Rochester Medical Center)

  • Minsoo Kim

    (University of Rochester Medical Center)

  • Lance C. Kam

    (Columbia University)

  • Khalid Salaita

    (Emory University)

  • Morgan Huse

    (Immunology Program, Memorial Sloan Kettering Cancer Center)

Abstract

Cytotoxic lymphocytes fight pathogens and cancer by forming immune synapses with infected or transformed target cells and then secreting cytotoxic perforin and granzyme into the synaptic space, with potent and specific killing achieved by this focused delivery. The mechanisms that establish the precise location of secretory events, however, remain poorly understood. Here we use single cell biophysical measurements, micropatterning, and functional assays to demonstrate that localized mechanotransduction helps define the position of secretory events within the synapse. Ligand-bound integrins, predominantly the αLβ2 isoform LFA-1, function as spatial cues to attract lytic granules containing perforin and granzyme and induce their fusion with the plasma membrane for content release. LFA-1 is subjected to pulling forces within secretory domains, and disruption of these forces via depletion of the adaptor molecule talin abrogates cytotoxicity. We thus conclude that lymphocytes employ an integrin-dependent mechanical checkpoint to enhance their cytotoxic power and fidelity.

Suggested Citation

  • Mitchell S. Wang & Yuesong Hu & Elisa E. Sanchez & Xihe Xie & Nathan H. Roy & Miguel Jesus & Benjamin Y. Winer & Elizabeth A. Zale & Weiyang Jin & Chirag Sachar & Joanne H. Lee & Yeonsun Hong & Minsoo, 2022. "Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30809-3
    DOI: 10.1038/s41467-022-30809-3
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    References listed on IDEAS

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    1. Yun Zhang & Chenghao Ge & Cheng Zhu & Khalid Salaita, 2014. "DNA-based digital tension probes reveal integrin forces during early cell adhesion," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    2. Jane C. Stinchcombe & Endre Majorovits & Giovanna Bossi & Stephen Fuller & Gillian M. Griffiths, 2006. "Centrosome polarization delivers secretory granules to the immunological synapse," Nature, Nature, vol. 443(7110), pages 462-465, September.
    3. Jane C. Stinchcombe & Endre Majorovits & Giovanna Bossi & Stephen Fuller & Gillian M. Griffiths, 2006. "Erratum: Centrosome polarization delivers secretory granules to the immunological synapse," Nature, Nature, vol. 444(7116), pages 236-236, November.
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    1. Claire Lacouture & Beatriz Chaves & Delphine Guipouy & Raïssa Houmadi & Valérie Duplan-Eche & Sophie Allart & Nicolas Destainville & Loïc Dupré, 2024. "LFA-1 nanoclusters integrate TCR stimulation strength to tune T-cell cytotoxic activity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Hyun-Kyu Choi & Peiwen Cong & Chenghao Ge & Aswin Natarajan & Baoyu Liu & Yong Zhang & Kaitao Li & Muaz Nik Rushdi & Wei Chen & Jizhong Lou & Michelle Krogsgaard & Cheng Zhu, 2023. "Catch bond models may explain how force amplifies TCR signaling and antigen discrimination," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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