Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells

In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking “back-differentiation” of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms.在发育中的B淋巴细胞（B lymphocyte）中，功能性V(D)J重链（heavy chain, HC）免疫球蛋白（immunoglobulin, Ig）重排可建立重链等位基因排斥（allelic exclusion），并向原B细胞（pro-B cell）传递发育信号，使其进展至前B细胞阶段。后续发生的功能性轻链（light chain, LC）重排，则会使未成熟B细胞（immature B cell stage）的表面表达IgM。 本研究证实，通过Cre介导的基因切除技术诱导性敲除细胞表面Ig，或用酪氨酸激酶抑制剂赫贝霉素A（herbimycin A）、磷脂酰肌醇3-激酶抑制剂渥曼青霉素（wortmannin）处理细胞以中断未成熟B细胞的基础IgM信号通路，可诱导细胞发生显著的“反向分化（back-differentiation）”，退回到B细胞发育的更早阶段，其特征为原B细胞基因的表达。 发生这种发育逆转的细胞同时还出现了新的轻链基因重排迹象，这表明基础Ig信号通路在维持轻链等位基因排斥过程中发挥着关键作用。本研究揭示了B细胞发育程序中此前未被认知的可塑性水平，对我们理解中枢耐受（central tolerance）机制具有重要的学术价值。