1. Immunology and Inflammation
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IFNγ induces epigenetic programming of human T-bethi B cells and promotesTLR7/8 and IL-21 induced differentiation

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Cite this article as: eLife 2019;8:e41641 doi: 10.7554/eLife.41641

Abstract

Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet drive autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNg signaling in human antibody responses is unknown. We show that elevated levels of IFNg in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNg or IFNg-producing T cells. IFNg promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNg signals poise B cells to differentiate by increasing their responsiveness to IL-21.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE95282 and GSE118984. All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files for sequencing analysis are included as Supplementary Files 1 and 2 (excel files).

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

Article and author information

Author details

  1. Esther Zumaquero

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sara L Stone

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1689-8148
  3. Christopher D Scharer

    Department of Microbiology and Immunology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7716-8504
  4. Scott A Jenks

    Department of Medicine, Division of Rheumatology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Anoma Nellore

    Department of Medicine, Division of Infectious Disease, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Betty Mousseau

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Antonio Rosal-Vela

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Davide Botta

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3926-0662
  9. John E Bradley

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Wojciech Wojciechowski

    Center for Pediatric Biomedical Research, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Travis Ptacek

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Maria I Danila

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jeffrey C Edberg

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. S Louis Bridges

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Robert P Kimberly

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. W Winn Chatham

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Trenton R Schoeb

    Department of Genetics, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Alexander F Rosenberg

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Jeremy M Boss

    Department of Microbiology and Immunology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Inaki Sanz

    Department of Medicine, Division of Rheumatology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Frances E Lund

    Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
    For correspondence
    flund@uab.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3083-1246

Funding

NIH Office of the Director (UL1 TR001417)

  • Travis Ptacek

NIH Office of the Director (1P30 DK079337)

  • Trenton R Schoeb

NIH Office of the Director (P01 AI078907)

  • Frances E Lund

NIH Office of the Director (R01 AI110508)

  • Frances E Lund

NIH Office of the Director (R01 AI123733)

  • Jeremy Boss

NIH Office of the Director (P01 AI125180)

  • Jeremy M Boss

NIH Office of the Director (R37 AI049660)

  • Sanz Inaki

NIH Office of the Director (U19 AI110483)

  • Sanz Inaki

NIH Office of the Director (T32 GM008361)

  • Sara L Stone

NIH Office of the Director (K23 AR062100)

  • Maria I Danila

Lupus Research Alliance (#550070)

  • Frances E Lund

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 procedures involving animals were approved by the UAB Institutional Animal Care and Use Committee and were conducted in accordance with the principles outlined by the National Research Council. UAB IACUC approval IACUC-09648 and IACUC-21203.

Human subjects: All subjects gave written informed consent for participation and provided peripheral blood for analysis. The UAB and Emory Human Subjects Institutional Review Board approved all study protocols for healthy donors and SLE patients. IRB protocols 160301002, X020805006, X140213002, and N140102003 for UAB and 58515 for Emory.

Reviewing Editor

  1. Facundo D Batista, Ragon Institute of MGH, MIT and Harvard, United States

Publication history

  1. Received: September 1, 2018
  2. Accepted: May 10, 2019
  3. Accepted Manuscript published: May 15, 2019 (version 1)
  4. Version of Record published: May 31, 2019 (version 2)

Copyright

© 2019, Zumaquero 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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