Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom.
Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom.
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3718-3727. doi: 10.1073/pnas.1915247117. Epub 2020 Feb 4.
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 and , 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.
B 细胞的发育可以被自身抗原正向或负向选择，但决定这些结果的机制尚不完全清楚。在这里，我们发现，在个体发生过程中，B 细胞内在的正选择和负选择之间的转换是由 Lin28b 向 let-7 基因表达的转变决定的。在小鼠 B 细胞中异位表达 Lin28b 转基因可恢复自身抗原在成年骨髓中对自身反应性 B-1 B 细胞的正向选择。对早期和晚期个体发生中抗原特异性未成熟 B 细胞的分析确定了与 B-1 B 细胞发育相关的 Lin28b 依赖性基因，包括 和 ，而 Lin28b 不依赖的效应与自身抗原的存在或缺失有关。这些发现确定了个体发生过程中 B 细胞命运的细胞内在和外在决定因素，并调和了 B 细胞发育的谱系和选择理论。它们解释了如何改变正选择和负选择之间的平衡，以适应个体一生中的免疫需求。
