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.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

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.

Reviewing Editor

  1. Michael L Dustin, University of Oxford, United Kingdom

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.

Version history

  1. Received: March 27, 2017
  2. Accepted: November 23, 2017
  3. Accepted Manuscript published: December 14, 2017 (version 1)
  4. Version of Record published: December 29, 2017 (version 2)
  5. Version of Record updated: January 2, 2018 (version 3)

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.

Metrics

  • 2,633
    Page views
  • 426
    Downloads
  • 17
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

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

Further reading

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Xinjian Ye, Yijing Bai ... Qianming Chen
    Research Article

    Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.