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Tracing Self-Reactive B Cells in Normal Mice

Takuya Nojima, Alexander E. Reynolds, Daisuke Kitamura, Garnett Kelsoe and Masayuki Kuraoka
J Immunol May 15, 2020, ji1901015; DOI: https://doi.org/10.4049/jimmunol.1901015
Takuya Nojima
*Department of Immunology, Duke University, Durham, NC 27710;
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Alexander E. Reynolds
*Department of Immunology, Duke University, Durham, NC 27710;
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Daisuke Kitamura
†Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan; and
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Garnett Kelsoe
*Department of Immunology, Duke University, Durham, NC 27710;
‡Duke Human Vaccine Institute, Duke University, Durham, NC 27710
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Masayuki Kuraoka
*Department of Immunology, Duke University, Durham, NC 27710;
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Key Points

  • Single-cell culture approach revealed B cell tolerance checkpoints in normal mice.

  • Self-reactivity is elevated in T3 and CD93+ and CD93− anergic B cells in spleen.

  • Both the lifespan and the signaling capacity of BCR vary among self-reactive B cells.

Abstract

BCR transgenic mice dominate studies of B cell tolerance; consequently, tolerance in normal mice expressing diverse sets of autoreactive B cells is poorly characterized. We have used single B cell cultures to trace self-reactivity in BCR repertoires across the first and second tolerance checkpoints and in tolerized B cell compartments of normal mice. This approach reveals affinity “setpoints” that define each checkpoint and a subset of tolerized, autoreactive B cells that is long-lived. In normal mice, the numbers of B cells avidly specific for DNA fall significantly as small pre-B become immature and transitional-1 B cells, revealing the first tolerance checkpoint. By contrast, DNA reactivity does not significantly change when immature and transitional-1 B cells become mature follicular B cells, showing that the second checkpoint does not reduce DNA reactivity. In the spleen, autoreactivity was high in transitional-3 (T3) B cells, CD93+IgM−/loIgDhi anergic B cells, and a CD93− anergic subset. Whereas splenic T3 and CD93+ anergic B cells are short-lived, CD93−IgM−/loIgDhi B cells have half-lives comparable to mature follicular B cells. B cell–specific deletion of proapoptotic genes, Bak and Bax, resulted in increased CD93−IgM−/loIgDhi B cell numbers but not T3 B cell numbers, suggesting that apoptosis regulates differently persistent and ephemeral autoreactive B cells. The self-reactivity and longevity of CD93−IgM−/loIgDhi B cells and their capacity to proliferate and differentiate into plasmacytes in response to CD40 activation in vitro lead us to propose that this persistent, self-reactive compartment may be the origin of systemic autoimmunity and a potential target for vaccines to elicit protective Abs cross-reactive with self-antigens.

Footnotes

  • This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (AI56363) and the Bill and Melinda Gates Foundation (to G.K.).

  • The online version of this article contains supplemental material.

  • Received August 21, 2019.
  • Accepted April 22, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Tracing Self-Reactive B Cells in Normal Mice
Takuya Nojima, Alexander E. Reynolds, Daisuke Kitamura, Garnett Kelsoe, Masayuki Kuraoka
The Journal of Immunology May 15, 2020, ji1901015; DOI: 10.4049/jimmunol.1901015

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Tracing Self-Reactive B Cells in Normal Mice
Takuya Nojima, Alexander E. Reynolds, Daisuke Kitamura, Garnett Kelsoe, Masayuki Kuraoka
The Journal of Immunology May 15, 2020, ji1901015; DOI: 10.4049/jimmunol.1901015
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Print ISSN 0022-1767        Online ISSN 1550-6606