Positive and negative selection shape the human naive B cell repertoire.
Positive and negative selection shape the human naive B cell repertoire.
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正选择和负选择形成人幼稚B细胞库。
DOI：
10.1172/jci150985
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发表时间：
2022-01-18
期刊：
影响因子：
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通讯作者：
Meffre E
中科院分区：
文献类型：
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作者：
Chen JW;Schickel JN;Tsakiris N;Sng J;Arbogast F;Bouis D;Parisi D;Gera R;Boeckers JM;Delmotte FR;Veselits M;Schuetz C;Jacobsen EM;Posovszky C;Schulz AS;Schwarz K;Clark MR;Menard L;Meffre E
尽管外周发育中的B细胞的负选择已得到很好的描述，但人们对其了解甚少，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，我们证明了在转运到外周幼稚B细胞池中时，表达的免疫球蛋白库存在强烈的偏斜。人源化小鼠中扩增的幼稚B细胞的这种阳性选择类似于在健康人供体中观察到的，并且不依赖于自体胸腺组织。相反，自身反应性B细胞的阴性选择需要胸腺来源的Tcl 4和由B细胞的MHC II类限制性自身抗原呈递。事实上，罕见裸淋巴细胞综合征患者的B细胞上的缺陷型MHC II类表达和人源化小鼠中通过HLA-DM抑制来预防自身抗原呈递都导致自身反应性幼稚B细胞的产生。这些后面的观察结果表明，TdR抑制自体反应幼稚B细胞连续产生的骨髓。因此，出现了一个模型，其中阳性和阴性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。
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.