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CTLA-4 expression by B-1a B cells is essential for immune tolerance

Author

Listed:
  • Yang Yang

    (Stanford University School of Medicine)

  • Xiao Li

    (Case Western Reserve University)

  • Zhihai Ma

    (Stanford University School of Medicine)

  • Chunlin Wang

    (iRepertoire Inc)

  • Qunying Yang

    (iRepertoire Inc)

  • Miranda Byrne-Steele

    (iRepertoire Inc)

  • Rongjian Hong

    (Fudan University)

  • Qing Min

    (Fudan University)

  • Gao Zhou

    (Case Western Reserve University)

  • Yong Cheng

    (St. Jude Children’s Research Hospital)

  • Guang Qin

    (Stanford University School of Medicine)

  • Justin V. Youngyunpipatkul

    (Stanford University School of Medicine)

  • James B. Wing

    (Osaka University
    Osaka University)

  • Shimon Sakaguchi

    (Osaka University)

  • Christian Toonstra

    (University of Maryland)

  • Lai-Xi Wang

    (University of Maryland)

  • Jose G. Vilches-Moure

    (Stanford University School of Medicine)

  • Denong Wang

    (SRI International Biosciences Division)

  • Michael P. Snyder

    (Stanford University School of Medicine)

  • Ji-Yang Wang

    (Fudan University
    Children’s Hospital of Fudan University
    Zhengzhou University)

  • Jian Han

    (iRepertoire Inc
    HudsonAlpha Institute for Biotechnology)

  • Leonore A. Herzenberg

    (Stanford University School of Medicine)

Abstract

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.

Suggested Citation

  • Yang Yang & Xiao Li & Zhihai Ma & Chunlin Wang & Qunying Yang & Miranda Byrne-Steele & Rongjian Hong & Qing Min & Gao Zhou & Yong Cheng & Guang Qin & Justin V. Youngyunpipatkul & James B. Wing & Shimo, 2021. "CTLA-4 expression by B-1a B cells is essential for immune tolerance," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20874-x
    DOI: 10.1038/s41467-020-20874-x
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