Abstract

Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced/peripheral regulatory T cells. To decipher the molecular mechanisms governing this process, we here focus on the TCR signaling cascade and demonstrate that a rise in intracellular calcium levels is sufficient to modulate the phenotype of mouse naive CD4 T cells and to increase their sensitivity to regulatory T-cell polarization signals, both processes relying on Calcineurin activation. Accordingly, in vivo Calcineurin inhibition leads the most Self-reactive naive CD4 T cells to adopt the phenotype of their less Self-reactive cell-counterparts. Collectively, our findings demonstrate that calcium-mediated activation of the Calcineurin pathway acts as a rheostat to shape both the phenotype and effector potential of naive CD4 T cells in the steady-state.

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Author details

  1. Vincent Guichard

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0206-4924
  2. Nelly Bonilla

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Aurélie Durand

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexandra Audemard-Verger

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas Guilbert

    Cell Biology of Host Pathogens Interactions, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Bruno Martin

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Bruno Lucas

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Cédric Auffray

    Infection, Immunity and Inflammation, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    For correspondence
    cedric.auffray@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1012-0132

Funding

Institut National de la Santé et de la Recherche Médicale

  • Nelly Bonilla
  • Alexandra Audemard-Verger
  • Thomas Guilbert
  • Bruno Martin
  • Bruno Lucas
  • Cédric Auffray

Agence Nationale de la Recherche (ANR-15-CE15-0009-01)

  • Cédric Auffray

Fondation pour la Recherche Médicale

  • Bruno Lucas

Ligue Contre le Cancer

  • Alexandra Audemard-Verger

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

Ethics

Animal experimentation: Experiments were carried out in accordance with the guidelines of the French Veterinary Department. All procedures performed were approved by the Paris-Descartes Ethical Committee for Animal Experimentation (decision CEEA34.CA.080.12). Sample sizes were chosen to ensure the reproducibility of the experiments and according to the 3Rs of animal ethics regulation.

Copyright

© 2017, Guichard 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. Vincent Guichard
  2. Nelly Bonilla
  3. Aurélie Durand
  4. Alexandra Audemard-Verger
  5. Thomas Guilbert
  6. Bruno Martin
  7. Bruno Lucas
  8. Cédric Auffray
(2017)
Calcium-mediated shaping of naive CD4 T-cell phenotype and function
eLife 6:e27215.
https://doi.org/10.7554/eLife.27215

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https://doi.org/10.7554/eLife.27215