Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation

  1. Antonio P Baptista
  2. Ramon Roozendaal
  3. Rogier M Reijmers
  4. Jasper J Koning
  5. Wendy W Unger
  6. Mascha Greuter
  7. Eelco D Keuning
  8. Rosalie Molenaar
  9. Gera Goverse
  10. Marlous M S Sneeboer
  11. Joke M M den Haan
  12. Marianne Boes
  13. Reina E Mebius  Is a corresponding author
  1. Vrije Universiteit Medical Center, Netherlands
  2. Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  3. University Medical Center Utrecht, Netherlands

Abstract

Non-hematopoietic lymph node stromal cells shape immunity by inducing MHC-I-dependent deletion of self-reactive CD8+ T cells and MHC-II-dependent anergy of CD4+ T cells. Here, we show that MHC-II expression on lymph node stromal cells is additionally required for homeostatic maintenance of regulatory T cells (Tregs) and maintenance of immune quiescence. In the absence of MHC-II expression in lymph node transplants, i.e. on lymph node stromal cells, CD4+ as well as CD8+ T cells became activated, ultimately resulting in transplant rejection. MHC-II self-antigen presentation by lymph node stromal cells allowed the non-proliferative maintenance of antigen-specific Tregs and constrained antigen-specific immunity. Altogether, our results reveal a novel mechanism by which lymph node stromal cells regulate peripheral immunity.

Article and author information

Author details

  1. Antonio P Baptista

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Ramon Roozendaal

    Janssen Center of Excellence for Immunoprophylaxis, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Rogier M Reijmers

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Jasper J Koning

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Wendy W Unger

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Mascha Greuter

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Eelco D Keuning

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Rosalie Molenaar

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Gera Goverse

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Marlous M S Sneeboer

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Joke M M den Haan

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Marianne Boes

    University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  13. Reina E Mebius

    Vrije Universiteit Medical Center, Amsterdam, Netherlands
    For correspondence
    r.mebius@vumc.nl
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Emil R Unanue, Washington University School of Medicine, United States

Ethics

Animal experimentation: All animal experiments were reviewed and approved by the Vrije University Scientific and Ethics Committees (protocols MCB09-35, MCB10-01 and MCB13-06). All surgery was performed under xylazine and ketamine anesthesia.

Version history

  1. Received: August 21, 2014
  2. Accepted: November 19, 2014
  3. Accepted Manuscript published: November 19, 2014 (version 1)
  4. Version of Record published: December 10, 2014 (version 2)

Copyright

© 2014, Baptista 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

  • 3,510
    views
  • 459
    downloads
  • 76
    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. Antonio P Baptista
  2. Ramon Roozendaal
  3. Rogier M Reijmers
  4. Jasper J Koning
  5. Wendy W Unger
  6. Mascha Greuter
  7. Eelco D Keuning
  8. Rosalie Molenaar
  9. Gera Goverse
  10. Marlous M S Sneeboer
  11. Joke M M den Haan
  12. Marianne Boes
  13. Reina E Mebius
(2014)
Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation
eLife 3:e04433.
https://doi.org/10.7554/eLife.04433

Share this article

https://doi.org/10.7554/eLife.04433

Further reading

    1. Immunology and Inflammation
    Xiuyuan Lu, Hiroki Hayashi ... Sho Yamasaki
    Research Article

    SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as ‘sustainers’), but not in ‘decliners’. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation
    Rajan M Thomas, Matthew C Pahl ... Andrew D Wells
    Research Article

    Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.