Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Illinois, USA.
J Clin Invest. 2022 Jan 18;132(2). doi: 10.1172/JCI150985.
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.
尽管外周发育中的 B 细胞的负选择已得到很好的描述，但仍知之甚少，而幼稚 B 细胞的正选择的证据仍然难以捉摸。使用 2 种人源化小鼠模型，我们证明在进入外周幼稚 B 细胞库时，表达的免疫球蛋白库发生了强烈的偏倚。这种在人源化小鼠中扩增的幼稚 B 细胞的正选择类似于在健康的人类供体中观察到的情况，并且独立于自体胸腺组织。相比之下，自身反应性 B 细胞的负选择需要来自胸腺的 Treg 和由 B 细胞呈递的 MHC Ⅱ类限制的自身抗原。事实上，在罕见的裸淋巴细胞综合征患者的 B 细胞中 MHC Ⅱ类表达缺陷，以及通过在人源化小鼠中抑制 HLA-DM 来防止自身抗原呈递，均导致产生了自身反应性幼稚 B 细胞。这些后一种观察结果表明，Treg 持续抑制骨髓中不断产生的自身反应性幼稚 B 细胞。因此，出现了一种模型，其中正选择和负选择共同塑造了人类幼稚 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。
