Division of Rheumatology, Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, California 94143, USA.
Nature. 2012 Sep 6;489(7414):160-4. doi: 10.1038/nature11311.
In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity. Yet, how B cells establish and maintain tolerance in the face of autoantigen exposure during and after development is not certain. Studies of model B-cell antigen receptor (BCR) transgenic systems have highlighted the critical role of functional unresponsiveness or ‘anergy’. Unlike T cells, evidence suggests that receptor editing and anergy, rather than deletion, account for much of B-cell tolerance. However, it remains unclear whether the mature diverse B-cell repertoire of mice contains anergic autoreactive B cells, and if so, whether antigen was encountered during or after their development. By taking advantage of a reporter mouse in which BCR signalling rapidly and robustly induces green fluorescent protein expression under the control of the Nur77 regulatory region, antigen-dependent and antigen-independent BCR signalling events in vivo during B-cell maturation were visualized. Here we show that B cells encounter antigen during development in the spleen, and that this antigen exposure, in turn, tunes the responsiveness of BCR signalling in B cells at least partly by downmodulating expression of surface IgM but not IgD BCRs, and by modifying basal calcium levels. By contrast, no analogous process occurs in naive mature T cells. Our data demonstrate not only that autoreactive B cells persist in the mature repertoire, but that functional unresponsiveness or anergy exists in the mature B-cell repertoire along a continuum, a fact that has long been suspected, but never yet shown. These results have important implications for understanding how tolerance in T and B cells is differently imposed, and how these processes might go awry in disease.
在人类中，多达 75%的新生成 B 细胞和约 30%的成熟 B 细胞显示出一定程度的自身反应性。然而，在发育过程中和发育后，B 细胞如何在面对自身抗原暴露时建立和维持耐受尚不确定。对模型 B 细胞抗原受体（BCR）转基因系统的研究强调了功能性无反应性或“失能”的关键作用。与 T 细胞不同，有证据表明，受体编辑和失能而不是删除，解释了 B 细胞耐受的大部分原因。然而，目前尚不清楚成熟的多样化小鼠 B 细胞库是否含有失能的自身反应性 B 细胞，如果是这样，那么这些 B 细胞是在其发育过程中还是在发育后遇到抗原的。通过利用一种报告小鼠，其中 BCR 信号在 Nur77 调节区的控制下迅速而强烈地诱导绿色荧光蛋白表达，在体内 B 细胞成熟过程中可视化了抗原依赖性和抗原非依赖性 BCR 信号事件。在这里，我们表明 B 细胞在脾脏发育过程中遇到抗原，而这种抗原暴露反过来又通过下调表面 IgM 但不 IgD BCR 的表达，以及通过改变基础钙水平，至少部分地调节 BCR 信号在 B 细胞中的反应性。相比之下，在幼稚成熟 T 细胞中没有类似的过程发生。我们的数据不仅表明自身反应性 B 细胞在成熟库中持续存在，而且功能无反应性或失能存在于成熟 B 细胞库中，这是一个长期以来被怀疑但从未被证明的事实。这些结果对于理解 T 细胞和 B 细胞中的耐受是如何不同地施加的，以及这些过程在疾病中如何出错具有重要意义。
