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LFA-1 nanoclusters integrate TCR stimulation strength to tune T-cell cytotoxic activity

Author

Listed:
  • Claire Lacouture

    (Toulouse III Paul Sabatier University
    Université de Toulouse, CNRS, UPS)

  • Beatriz Chaves

    (Toulouse III Paul Sabatier University
    Oswaldo Cruz Foundation (Fiocruz)
    Oswaldo Cruz Foundation (Fiocruz))

  • Delphine Guipouy

    (Toulouse III Paul Sabatier University)

  • Raïssa Houmadi

    (Toulouse III Paul Sabatier University)

  • Valérie Duplan-Eche

    (Toulouse III Paul Sabatier University)

  • Sophie Allart

    (Toulouse III Paul Sabatier University)

  • Nicolas Destainville

    (Université de Toulouse, CNRS, UPS)

  • Loïc Dupré

    (Toulouse III Paul Sabatier University
    Medical University of Vienna)

Abstract

T-cell cytotoxic function relies on the cooperation between the highly specific but poorly adhesive T-cell receptor (TCR) and the integrin LFA-1. How LFA-1-mediated adhesion may scale with TCR stimulation strength is ill-defined. Here, we show that LFA-1 conformation activation scales with TCR stimulation to calibrate human T-cell cytotoxicity. Super-resolution microscopy analysis reveals that >1000 LFA-1 nanoclusters provide a discretized platform at the immunological synapse to translate TCR engagement and density of the LFA-1 ligand ICAM-1 into graded adhesion. Indeed, the number of high-affinity conformation LFA-1 nanoclusters increases as a function of TCR triggering strength. Blockade of LFA-1 conformational activation impairs adhesion to target cells and killing. However, it occurs at a lower TCR stimulation threshold than lytic granule exocytosis implying that it licenses, rather than directly controls, the killing decision. We conclude that the organization of LFA-1 into nanoclusters provides a calibrated system to adjust T-cell killing to the antigen stimulation strength.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44688-3
    DOI: 10.1038/s41467-024-44688-3
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    References listed on IDEAS

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    1. Sinem K. Saka & Alf Honigmann & Christian Eggeling & Stefan W. Hell & Thorsten Lang & Silvio O. Rizzoli, 2014. "Multi-protein assemblies underlie the mesoscale organization of the plasma membrane," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    2. 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.
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