Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses

  1. Sara G Dosil
  2. Sheila Lopez-Cobo
  3. Ana Rodriguez-Galan
  4. Irene Fernandez-Delgado
  5. Marta Ramirez-Huesca
  6. Paula Milan-Rois
  7. Milagros Castellanos
  8. Alvaro Somoza
  9. Manuel J Gómez
  10. Hugh T Reyburn
  11. Mar Vales-Gomez
  12. Francisco Sánchez Madrid  Is a corresponding author
  13. Lola Fernandez-Messina  Is a corresponding author
  1. Universidad Autónoma de Madrid, Spain
  2. INSERM U932, Institut Curie, PSL Research University, France
  3. National Center for Cardiovascular Research, Spain
  4. Unidad Asociada al Centro Nacional de Biotecnología, Spain
  5. Spanish National Research Council, Spain

Abstract

Natural killer (NK) cells recognise and kill target cells undergoing different types of stress. NK cells are also capable of modulating immune responses. In particular, they regulate T cell functions. Small RNA next-generation sequencing of resting and activated human NK cells and their secreted EVs led to the identification of a specific repertoire of NK-EV-associated microRNAs and their post-transcriptional modifications signature. Several microRNAs of NK-EVs, namely miR-10b-5p, miR-92a-3p and miR-155-5p, specifically target molecules involved in Th1 responses. NK-EVs promote the downregulation of GATA3 mRNA in CD4+ T cells and subsequent TBX21 de-repression that leads to Th1 polarization and IFN-γ and IL-2 production. NK-EVs also have an effect on monocyte and moDCs function, driving their activation and increased presentation and co-stimulatory functions. Nanoparticle-delivered NK-EV microRNAs partially recapitulate NK-EV effects in mice. Our results provide new insights on the immunomodulatory roles of NK-EVs that may help to improve their use as immunotherapeutic tools.

Data availability

Sequencing data have been deposited in the Gene Expression Omnibus and are available to readers under record GSE185171. EV isolation procedures are available at EV‐TRACK knowledgebase (EV‐TRACK ID: EV210234.

The following data sets were generated

Article and author information

Author details

  1. Sara G Dosil

    Servicio de Inmunología, Universidad Autónoma de Madrid, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Sheila Lopez-Cobo

    INSERM U932, Institut Curie, PSL Research University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Ana Rodriguez-Galan

    Servicio de Inmunología, Universidad Autónoma de Madrid, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6209-782X
  4. Irene Fernandez-Delgado

    Servicio de Inmunología, Universidad Autónoma de Madrid, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Marta Ramirez-Huesca

    Vascular Pathophysiology Area, National Center for Cardiovascular Research, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Paula Milan-Rois

    Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) & Nanobiotecnología (IMDEA-Nanociencia), Unidad Asociada al Centro Nacional de Biotecnología, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7043-2920
  7. Milagros Castellanos

    Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) & Nanobiotecnología (IMDEA-Nanociencia), Unidad Asociada al Centro Nacional de Biotecnología, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Alvaro Somoza

    Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia) & Nanobiotecnología (IMDEA-Nanociencia), Unidad Asociada al Centro Nacional de Biotecnología, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Manuel J Gómez

    Vascular Pathophysiology Area, National Center for Cardiovascular Research, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Hugh T Reyburn

    Department of Immunology and Oncology, Spanish National Research Council, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. Mar Vales-Gomez

    Department of Immunology and Oncology, Spanish National Research Council, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  12. Francisco Sánchez Madrid

    Servicio de Inmunología, Universidad Autónoma de Madrid, Madrid, Spain
    For correspondence
    fsmadrid@salud.madrid.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5303-0762
  13. Lola Fernandez-Messina

    Servicio de Inmunología, Universidad Autónoma de Madrid, Madrid, Spain
    For correspondence
    lfernandezmessina@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2163-8746

Funding

Spanish National Plan for Scientific and Technical Research and Innovation (PD1-2020-120412RB-100)

  • Francisco Sánchez Madrid

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental methods and protocols were approved by the CNIC and the Comunidad Autónoma de Madrid and conformed to European Commission guidelines and regulations (PROEX-206.1/20)

Copyright

© 2022, Dosil et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sara G Dosil
  2. Sheila Lopez-Cobo
  3. Ana Rodriguez-Galan
  4. Irene Fernandez-Delgado
  5. Marta Ramirez-Huesca
  6. Paula Milan-Rois
  7. Milagros Castellanos
  8. Alvaro Somoza
  9. Manuel J Gómez
  10. Hugh T Reyburn
  11. Mar Vales-Gomez
  12. Francisco Sánchez Madrid
  13. Lola Fernandez-Messina
(2022)
Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses
eLife 11:e76319.
https://doi.org/10.7554/eLife.76319

Share this article

https://doi.org/10.7554/eLife.76319

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