Tracing Self-Reactive B Cells in Normal Mice

• Published in: The Journal of immunology (1950) 2020-07, Vol.205 (1), p.90-101
• Main Authors: Nojima, Takuya, Reynolds, Alexander E, Kitamura, Daisuke, Kelsoe, Garnett, Kuraoka, Masayuki
• Format: Article
• Language: English
• Subjects: Animals; Autoantigens - immunology; Autoantigens - metabolism; Autoimmunity; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cells, Cultured; Clonal Anergy; Cross Reactions; Half-Life; Lymph Nodes - cytology; Lymph Nodes - immunology; Mice; Models, Animal; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - metabolism; Primary Cell Culture; Receptors, Antigen, B-Cell - metabolism; Single-Cell Analysis; Spleen - cytology; Spleen - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1901015

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 IgD anergic B cells, and a CD93 anergic subset. Whereas splenic T3 and CD93 anergic B cells are short-lived, CD93 IgM IgD B cells have half-lives comparable to mature follicular B cells. B cell-specific deletion of proapoptotic genes, and , resulted in increased CD93 IgM IgD 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 IgD 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.