T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction
T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction
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T-B 细胞缠结和 ICOSL 驱动的生发中心反应前馈调节
DOI：
10.1038/nature13803
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发表时间：
2015-01-08
期刊：
影响因子：
64.8
通讯作者：
Qi, Hai
中科院分区：
文献类型：
--
作者：
Liu, Dan;Xu, Heping;Qi, Hai
生发中心(GC)反应支持基于亲和力的B细胞竞争，并产生高亲和力的骨髓浆细胞(BMPC)(1，2)。滤泡辅助性T细胞(T-FH)如何调控GC选择尚不清楚(3，4)。使用竞争性混合嵌合体，我们在这里表明，除了在促进T-FH发育的作用(5-7)之外，ICOSL(可诱导T细胞共刺激配体，也称为ICOSLG)对于单个B细胞竞争性地参与GC反应并发育为BMPC是重要的。利用钙离子报告分子辅助的活体成像，我们进一步显示ICOSL促进T-FH-B细胞相互作用的“纠缠”模式，其特征是短暂但广泛的表面接触，产生T细胞钙尖峰，以及B细胞获取CD40信号。反复的纠缠促进了竞争对手GC B细胞和T-FH细胞的外区共定位，为前者提供了更多获得T细胞帮助的机会。CD40信号上调GC B细胞表面ICOSL。接触依赖的Help和ICOSL控制的纠缠之间的这种细胞间正反馈促进了正选择和BMPC的发展，观察到高亲和力的B细胞受体变体富含在ICOSL高组份中，数字上处于劣势的ICOSL缺乏的GC B细胞或BMPC在竞争嵌合体中显示出强大的亲和力补偿，当GC竞争在没有ICOSL的情况下进行时，在其他正常GC反应中对高亲和力变体的选择受到损害。通过证明缠结是GC T-FH-B细胞相互作用的基本形式，确认ICOSL是T-B相互作用动力学和高亲和力BMPC形成的正选择之间的分子连锁，我们的研究揭示了T-FH细胞控制长期体液免疫质量的途径。
The germinal centre(GC) reaction supports affinity-based B-cell competition and generates high-affinity bone-marrow plasma cells (BMPCs)(1,2). How follicular T-helper (T-FH) cells regulate GC selection is not clear(3,4). Using competitive mixed chimaera, we show here that, beyond the role in promoting T-FH development(5-7), ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) is important for individual B cells to competitively participate in the GC reaction and to develop into BMPCs. Using intravital imaging aided by a calcium reporter, we further show that ICOSL promotes an 'entangled' mode of T-FH-B-cell interactions, characterized by brief but extensive surface engagement, productive T-cell calcium spikes, and B-cell acquisition of CD40 signals. Reiterated entanglement promotes outer-zone co-localization of outcompeting GC B cells together with T-FH cells, affording the former increased access to T-cell help. ICOSL on GC B cells is upregulated by CD40 signals. Such an intercellular positive feedback between contact-dependent help and ICOSL-controlled entanglement promotes positive selection and BMPC development, as evidenced by observations that higher-affinity B-cell receptor variants are enriched in the ICOSLhigh fraction, that numerically disadvantaged ICOSL-deficient GC B cells or BMPCs exhibit strong affinity compensation in competitive chimaera, and that when GC competition proceeds without ICOSL, selection of high-affinity variants in otherwise normal GC reactions is impaired. By demonstrating entanglement as the basic form of GC T-FH-B-cell interactions, identifying ICOSL as a molecular linkage between T-B interactional dynamics and positive selection for high-affinity BMPC formation, our study reveals a pathway by which T-FH cells control the quality of long-lived humoral immunity.