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- 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;
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- Masayuki Kuraoka
- *Department of Immunology, Duke University, Durham, NC 27710;
説明
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
収録刊行物
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- The Journal of Immunology
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The Journal of Immunology 205 (1), 90-101, 2020-07-01
Oxford University Press (OUP)
