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Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation

Lindsay E. Nyhoff, Amber S. Griffith, Emily S. Clark, James W. Thomas, Wasif N. Khan and Peggy L. Kendall
J Immunol December 15, 2021, 207 (12) 2922-2932; DOI: https://doi.org/10.4049/jimmunol.2000558
Lindsay E. Nyhoff
*Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN;
†Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN;
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Amber S. Griffith
‡Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO;
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Emily S. Clark
§Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL; and
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James W. Thomas
*Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN;
¶Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
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Wasif N. Khan
§Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL; and
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Peggy L. Kendall
*Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN;
†Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN;
‡Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO;
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Key Points

  • Btk supports autoreactive B cells through an early immune tolerance checkpoint.

  • Btk mediates antiapoptotic Bcl-xL expression in anergic anti-insulin B cells.

  • Mature autoreactive B cells do not require Btk for survival or Ag presentation.

Abstract

Bruton’s tyrosine kinase (Btk) propagates B cell signaling, and BTK inhibitors are in clinical trials for autoimmune disease. Although autoreactive B cells fail to develop in the absence of Btk, its role in mature cells is unknown. To address this issue, a model of conditional removal (Btkflox/Cre-ERT2) was used to excise Btk from mature transgenic B cells that recognize the pathophysiologic autoantigen insulin. Anti-insulin B cells escape central tolerance and promote autoimmune diabetes, mimicking human autoreactive cells. Lifelong Btk deficiency was previously shown to eliminate 95% of anti-insulin B cells, but in this model, mature anti-insulin B cells survived for weeks after targeted Btk deletion, even when competing with a polyclonal repertoire. BCR-stimulated cells could still signal via Syk, PLCy2, and CD22, but failed to upregulate the antiapoptotic protein Bcl-xL, and proliferation was impaired. Surprisingly, Btk-depleted anti-insulin B cells could still present Ag and activate T cells, a critical function in promoting T cell–mediated islet cell destruction. Thus, pharmacologic targeting of Btk may be most effective by blocking expansion of established autoreactive cells, and preventing emergence of new ones.

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Footnotes

  • This work was supported by Department of Veterans’ Affairs Merit Award I01 BX 002882 (P.L.K.); by National Institutes of Health Grants: National Institute of Diabetes and Digestive and Kidney Diseases R01 DK084246 (P.L.K.), R01 AI051448-16 (J.W.T.), R01 AI060729 (W.N.K.), P30 A1073961 (E.S.C.), and T32HL069765 (L.E.N.); and by the Jeffrey Modell Foundation (W.N.K.). Flow cytometry experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource. The Vanderbilt University Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Btkflox mice were generated at the transgenic core, Miller School of Medicine, University of Miami.

  • L.E.N. performed all 125Tg mouse experiments, analyzed and interpreted the data, and wrote the manuscript; A.S.G. performed all VH125Tg mouse experiments, analyzed and interpreted the data, and assisted in writing the Results section for the corresponding experiments; E.S.C., W.N.K., and J.W.T. developed the mouse models and participated in manuscript planning and experimental design; J.W.T. and W.N.K. edited the manuscript; and P.L.K. designed and supervised all aspects of the project and edited the manuscript.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    Btk
    Bruton’s tyrosine kinase
    cRPMI
    complete RPMI
    FO
    follicular
    MZ
    marginal zone
    pMZ
    premarginal zone
    T1
    early transitional
    T2
    late transitional
    T1D
    type 1 diabetes

  • Received May 14, 2020.
  • Accepted September 29, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 207 (12)
The Journal of Immunology
Vol. 207, Issue 12
15 Dec 2021
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Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation
Lindsay E. Nyhoff, Amber S. Griffith, Emily S. Clark, James W. Thomas, Wasif N. Khan, Peggy L. Kendall
The Journal of Immunology December 15, 2021, 207 (12) 2922-2932; DOI: 10.4049/jimmunol.2000558

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Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation
Lindsay E. Nyhoff, Amber S. Griffith, Emily S. Clark, James W. Thomas, Wasif N. Khan, Peggy L. Kendall
The Journal of Immunology December 15, 2021, 207 (12) 2922-2932; DOI: 10.4049/jimmunol.2000558
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