Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis

  1. Gerdien Mijnheer
  2. Nila Hendrika Servaas
  3. Jing Yao Leong
  4. Arjan Boltjes
  5. Eric Spierings
  6. Phyllis Chen
  7. Liyun Lai
  8. Alessandra Petrelli
  9. Sebastiaan Vastert
  10. Rob J de Boer
  11. Salvatore Albani
  12. Aridaman Pandit  Is a corresponding author
  13. Femke van Wijk  Is a corresponding author
  1. University Medical Center Utrecht, Netherlands
  2. SingHealth Duke-NUS Academic Medical Centre, Singapore
  3. Utrecht University, Netherlands

Abstract

Autoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in Juvenile Idiopathic Arthritis (JIA). We studied different joints affected at the same time, as well as over the course of relapsing-remitting disease. We found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient, and observed a strong overlap between dominant T cell clones, especially Treg, of which some could also be detected in circulation and persisted over the course of relapsing remitting disease. Moreover, these T cell clones were characterized by a high degree of sequence similarity, indicating the presence of TCR clusters responding to the same antigens. These data suggest that in localized autoimmune disease there is auto-antigen driven expansion of both Teffector and Treg clones, that are highly persistent and are (re)circulating. These dominant clones might represent interesting therapeutic targets.

Data availability

TCR-sequencing data presented in this study have been deposited in NCBI's Gene Expression Omnibus (GEO) database under GSE196301. Both raw data and processed data are available.

The following data sets were generated

Article and author information

Author details

  1. Gerdien Mijnheer

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Nila Hendrika Servaas

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9825-7554
  3. Jing Yao Leong

    Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Arjan Boltjes

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Eric Spierings

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9441-1019
  6. Phyllis Chen

    Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Liyun Lai

    Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Alessandra Petrelli

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Sebastiaan Vastert

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Rob J de Boer

    Theoretical Biology, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2130-691X
  11. Salvatore Albani

    Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  12. Aridaman Pandit

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    For correspondence
    A.Pandit@umcutrecht.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2057-9737
  13. Femke van Wijk

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    For correspondence
    F.vanWijk@umcutrecht.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8343-1356

Funding

ZonMw (91714332)

  • Femke van Wijk

Netherlands Organisation for Scientific Research (016.Veni.178.027)

  • Aridaman Pandit

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

Ethics

Human subjects: Informed consent was obtained from all patients either directly or from parents/guardians when the patients were younger than 12 years of age. The study was conducted in accordance with the Institutional Review Board of the University Medical Center Utrecht (approval no. 11-499/C), in compliance with the Declaration of Helsinki.

Reviewing Editor

  1. Di Chen, Chinese Academy of Sciences, China

Publication history

  1. Received: March 29, 2022
  2. Accepted: January 20, 2023
  3. Accepted Manuscript published: January 23, 2023 (version 1)

Copyright

© 2023, Mijnheer 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. Gerdien Mijnheer
  2. Nila Hendrika Servaas
  3. Jing Yao Leong
  4. Arjan Boltjes
  5. Eric Spierings
  6. Phyllis Chen
  7. Liyun Lai
  8. Alessandra Petrelli
  9. Sebastiaan Vastert
  10. Rob J de Boer
  11. Salvatore Albani
  12. Aridaman Pandit
  13. Femke van Wijk
(2023)
Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis
eLife 12:e79016.
https://doi.org/10.7554/eLife.79016

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