Endogenous antigen tunes the responsiveness of naive B cells but not T cells.
Endogenous antigen tunes the responsiveness of naive B cells but not T cells.
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DOI：
10.1038/nature11311
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发表时间：
2012-09-06
期刊：
影响因子：
64.8
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
--
作者：
Zikherman, Julie;Parameswaran, Ramya;Weiss, Arthur
在人类中，高达75%的新产生的B细胞和约30%的成熟B细胞表现出一定程度的自身反应性。然而，B细胞如何在发育过程中和发育后面对自身抗原暴露建立和维持耐受性尚不确定。模型BCR转基因系统的研究强调了功能性无反应或“无能量”所起的关键作用。与T细胞不同，有证据表明，受体编辑和无反应性，而不是删除，占B细胞耐受性的大部分。然而，目前还不清楚小鼠成熟的多样性B细胞库是否包含无反应性自身反应性B细胞，如果是这样，是否在其发育过程中或之后遇到抗原。通过利用报道小鼠，其中B细胞抗原受体（BCR）信号传导在Nur 77调节区的控制下快速且稳健地诱导GFP表达，在B细胞成熟期间体内抗原依赖性和非依赖性BCR信号传导事件被可视化。在这里，我们表明，B细胞遇到抗原在脾脏中的发展过程中，这种抗原暴露反过来调谐BCR信号在B细胞的反应，至少部分通过下调表面IgM的表达，但不是IgD BCR，并通过修改基础钙水平。相比之下，幼稚成熟T细胞中没有类似的过程。我们的数据表明，不仅自身反应性B细胞持续存在于成熟的库，但功能性无反应性或“无反应性”存在于成熟的B细胞库沿着一个连续体，一个事实，一直怀疑，但从未显示。这些结果对于理解T细胞和B细胞的耐受性是如何不同地施加的，以及这些过程在疾病中是如何出错的具有重要意义。
In humans up to 75% of newly generated B cells and about 30% of mature B cells exhibit 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 BCR transgenic systems have highlighted the critical role played by 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 B cell antigen receptor (BCR) signaling rapidly and robustly induces GFP expression under the control of the Nur77 regulatory region, antigen-dependent and – independent BCR signaling 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 signaling in B cells at least partly by down-modulating 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.
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影响因子：
8.7
作者：
Yarkoni Y;Getahun A;Cambier JC
通讯作者：
Cambier JC
DOI：
10.1084/jem.179.2.425
发表时间：
1994-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cooke MP;Heath AW;Shokat KM;Zeng Y;Finkelman FD;Linsley PS;Howard M;Goodnow CC
通讯作者：
Goodnow CC
脾脏中的B细胞发育发生在离散的步骤中，并取决于B细胞受体衍生的信号的质量。
影响因子：
15.3
作者：
Loder, F;Mutschler, B;Ray, R J;Paige, C J;Sideras, P;Torres, R;Lamers, M C;Carsetti, R
通讯作者：
Carsetti, R
DOI：
10.1084/jem.186.9.1513
发表时间：
1997-11-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lang J;Arnold B;Hammerling G;Harris AW;Korsmeyer S;Russell D;Strasser A;Nemazee D
通讯作者：
Nemazee D
影响因子：
32.4
作者：
Cornall, RJ;Cyster, JG;Goodnow, CC
通讯作者：
Goodnow, CC