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Developing B cells can be positively or negatively selected by self-antigens, but the mechanisms that determine these outcomes are incompletely understood. Here, we show that a B cell intrinsic switch between positive and negative selection during ontogeny is determined by a change from Lin28b to let-7 gene expression. Ectopic expression of a Lin28b transgene in murine B cells restored the positive selection of autoreactive B-1 B cells by self-antigen in adult bone marrow. Analysis of antigen-specific immature B cells in early and late ontogeny identified Lin28b-dependent genes associated with B-1 B cell development, including Arid3a and Bhleh41, and Lin28b-independent effects are associated with the presence or absence of self-antigen. These findings identify cell intrinsic and extrinsic determinants of B cell fate during ontogeny and reconcile lineage and selection theories of B cell development. They explain how changes in the balance of positive and negative selection may be able to adapt to meet the immunological needs of an individual during its lifetime.

Original publication

DOI

10.1073/pnas.1915247117

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

18/02/2020

Volume

117

Pages

3718 - 3727

Keywords

B cell, ontogeny, selection, Animals, B-Lymphocytes, Cell Proliferation, Mice, Mice, Inbred C57BL, MicroRNAs, RNA-Binding Proteins