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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