Functionally specialized human CD4+ T cell subsets express physicochemically distinct TCRs

  1. Sofia A Kasatskaya
  2. Kristin Ladell
  3. Evgeniy S Egorov
  4. Kelly L Miners
  5. Alexey N Davydov
  6. Maria Metsger
  7. Dmitry B Staroverov
  8. Elena K Matveishina
  9. Irina A Shagina
  10. Ilgar Z Mamedov
  11. Mark Izraelson
  12. Pavel V Shelyakin
  13. Olga V Britanova
  14. David A Price
  15. Dmitriy M Chudakov  Is a corresponding author
  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Federation
  2. Cardiff University School of Medicine, United Kingdom
  3. Central European Institute of Technology, Czech Republic
  4. Lomonosov Moscow State University, Russian Federation

Abstract

The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the ab TCR repertoires of human naive and effector/memory CD4+ T cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

Data availability

All extracted repertoires and metadata are deposited in Figshare: https://figshare.com/s/2145b1b16c6854445af7 and https://figshare.com/s/84ec5f412356afb0536d.

The following data sets were generated

Article and author information

Author details

  1. Sofia A Kasatskaya

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  2. Kristin Ladell

    Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Evgeniy S Egorov

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  4. Kelly L Miners

    Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Alexey N Davydov

    Adaptive Immunity Group, Central European Institute of Technology, Brno, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  6. Maria Metsger

    Adaptive Immunity Group, Central European Institute of Technology, Brno, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  7. Dmitry B Staroverov

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  8. Elena K Matveishina

    Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4641-4906
  9. Irina A Shagina

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  10. Ilgar Z Mamedov

    Department of Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  11. Mark Izraelson

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  12. Pavel V Shelyakin

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  13. Olga V Britanova

    Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  14. David A Price

    Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9416-2737
  15. Dmitriy M Chudakov

    Department of Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    For correspondence
    chudakovdm@mail.ru
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0430-790X

Funding

Ministry of Science and Higher Eductaion of Russian Federation (075-15-2019-1789)

  • Dmitriy M Chudakov

Wellcome Trust (100326/Z/12/Z)

  • David A Price

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

Ethics

Human subjects: Ethical approval was granted by the institutional review committees at Cardiff University School of Medicine (reference number 16/55) and the Pirogov Russian National Research Medical University (protocol number 2017/52) and all donors provided informed consent for their participation in the study.

Copyright

© 2020, Kasatskaya 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

  • 2,785
    views
  • 375
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Sofia A Kasatskaya
  2. Kristin Ladell
  3. Evgeniy S Egorov
  4. Kelly L Miners
  5. Alexey N Davydov
  6. Maria Metsger
  7. Dmitry B Staroverov
  8. Elena K Matveishina
  9. Irina A Shagina
  10. Ilgar Z Mamedov
  11. Mark Izraelson
  12. Pavel V Shelyakin
  13. Olga V Britanova
  14. David A Price
  15. Dmitriy M Chudakov
(2020)
Functionally specialized human CD4+ T cell subsets express physicochemically distinct TCRs
eLife 9:e57063.
https://doi.org/10.7554/eLife.57063

Share this article

https://doi.org/10.7554/eLife.57063

Further reading

    1. Immunology and Inflammation
    Yue Yang, Bin Huang ... Fangfang Zhang
    Research Article

    Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

    1. Immunology and Inflammation
    Josep Garnica, Patricia Sole ... Pere Santamaria
    Research Article

    Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10, are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.