Abstract

Tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. Yet, if and how the tissue environment shapes the antigen specificity of iNKT cells remains unknown. By analysing iNKT cells from lymphoid tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for cells from various tissues resulting in differential lipid-antigen recognition. Within peripheral tissues iNKT cell recent thymic emigrants exhibit a different TCR repertoire than mature cells, suggesting that the iNKT population is shaped after arrival to the periphery. Consistent with this, iNKT cells from different organs show distinct basal activation, proliferation and clonal expansion. Moreover, the iNKT cell TCR repertoire changes following immunisation and is shaped by age and environmental changes. Thus, post-thymic modification of the TCR-repertoire underpins the distinct antigen specificity for iNKT cells in peripheral tissues.

Data availability

The RNAseq data are available in the Gene Expression Omnibus (GEO) database with accession number GSE131420.

The following data sets were generated

Article and author information

Author details

  1. Rebeca Jimeno

    The Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Marta Lebrusant-Fernandez

    The Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Christian Margreitter

    Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Beth Lucas

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Natacha Veerapen

    Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Gurdyal S Besra

    Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Franca Fraternali

    Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3143-6574
  8. Jo Spencer

    The Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Graham Anderson

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Patricia Barral

    The Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    For correspondence
    patricia.barral@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4324-8973

Funding

Medical Research Council (MR/L008157/1)

  • Patricia Barral

Marie Curie Intraeuropean Fellowship (H2020-MSCA-IF-2015-703639)

  • Rebeca Jimeno

Medical Research Council (DKAA.RRAK18742)

  • Graham Anderson

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 animal experiments were approved by the Francis Crick Institute's and the King's College London's Animal Welfare and Ethical Review Body and the United Kingdom Home Office.

Human subjects: Human tissues used in this study were collected with ethical approval from UK Research Ethics Committees administered through the Integrated Research Application System. All samples were collected with informed consent.

Reviewing Editor

  1. Chyung-Ru Wang, Northwestern University, United States

Version history

  1. Received: September 5, 2019
  2. Accepted: December 15, 2019
  3. Accepted Manuscript published: December 16, 2019 (version 1)
  4. Version of Record published: December 24, 2019 (version 2)
  5. Version of Record updated: March 18, 2020 (version 3)

Copyright

© 2019, Jimeno 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

  • 2,828
    Page views
  • 428
    Downloads
  • 10
    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. Rebeca Jimeno
  2. Marta Lebrusant-Fernandez
  3. Christian Margreitter
  4. Beth Lucas
  5. Natacha Veerapen
  6. Gurdyal S Besra
  7. Franca Fraternali
  8. Jo Spencer
  9. Graham Anderson
  10. Patricia Barral
(2019)
Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells
eLife 8:e51663.
https://doi.org/10.7554/eLife.51663

Further reading

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Roshni Roy, Pei-Lun Kuo ... Luigi Ferrucci
    Research Article Updated

    Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4+ and CD8+ T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor (TF) motifs, respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to TF motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.