Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II–restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.

中文翻译：

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正负选择塑造了人类幼稚 B 细胞库

尽管对周围发育中的 B 细胞的负选择进行了很好的描述，但对其知之甚少，但幼稚 B 细胞正选择的证据仍然难以捉摸。使用 2 个人源化小鼠模型，我们证明在转移到外周幼稚 B 细胞池时，表达的免疫球蛋白库有很强的偏差。这种在人源化小鼠中扩增的幼稚 B 细胞的阳性选择类似于在健康人类供体中观察到的，并且不依赖于自体胸腺组织。相比之下，自身反应性 B 细胞的负选择需要胸腺衍生的 Tregs 和 MHC II 类限制 B 细胞的自身抗原呈递。确实，罕见裸淋巴细胞综合征患者的 B 细胞上 MHC II 类表达缺陷和通过抑制人源化小鼠的 HLA-DM 来预防自身抗原呈递均导致自身反应性幼稚 B 细胞的产生。后面的这些观察表明，Tregs 抑制了由骨髓持续产生的自身反应性幼稚 B 细胞。因此，出现了一个模型，其中正选择和负选择都塑造了人类幼稚 B 细胞库，并且每个过程都由根本不同的分子和细胞机制介导。