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Self-activation of Vγ9Vδ2 T cells by exogenous phosphoantigens involves TCR and butyrophilins

Cellular & Molecular Immunology volume 18, pages 1861–1870 (2021)Cite this article

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Abstract

The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies. However, the molecular mechanism of their activation by phosphoantigens (PAgs) is not completely known. Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells, such as immune presenting cells or tumor cells. In this study, we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs, involving their TCR and the butyrophilins BTN3A1 and BTN2A1. This is the first time that these three molecules, concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells, have been shown to be involved together on the same and unique T cell during PAg activation. Moreover, the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed by γ9TCR, BTN3A1 and BTN2A1. The self-activation of Vγ9Vδ2 T cells, which leads to self-killing, can therefore participate in the failure of γδ T cell-based therapies with exogenous PAgs and should be taken into account.

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Acknowledgements

This work was funded by INSERM, CNRS, the University Hospital of Bordeaux, and Toulouse III University. We acknowledge ImCheck for providing the 103.2 antibody and the 7.48 antibody. We are grateful to our healthcare professionals for their boundless efforts during the COVID-19 crisis.

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Authors and Affiliations

  1. Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France

    Chloé Laplagne, Laetitia Ligat, Juliet Foote, Frederic Lopez, Jean-Jacques Fournié, Camille Laurent, Salvatore Valitutti & Mary Poupot

  2. Université Toulouse III Paul-Sabatier, Toulouse, France

    Chloé Laplagne, Laetitia Ligat, Juliet Foote, Frederic Lopez, Jean-Jacques Fournié, Camille Laurent, Salvatore Valitutti & Mary Poupot

  3. ERL 5294 CNRS, Toulouse, France

    Chloé Laplagne, Laetitia Ligat, Juliet Foote, Frederic Lopez, Jean-Jacques Fournié, Camille Laurent, Salvatore Valitutti & Mary Poupot

  4. IUCT-O, Toulouse, France

    Camille Laurent

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  1. Chloé Laplagne
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C Laplagne performed the experiments. LL and FL participated in the microscopic experiments. JJF, CLaurent and SV participated in the discussion of the results. JF reviewed the English language. MP and CLaplagne designed the experiments and wrote the paper. MP supervised the study.

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Correspondence to Mary Poupot.

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Laplagne, C., Ligat, L., Foote, J. et al. Self-activation of Vγ9Vδ2 T cells by exogenous phosphoantigens involves TCR and butyrophilins. Cell Mol Immunol 18, 1861–1870 (2021). https://doi.org/10.1038/s41423-021-00720-w

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