Plasmablasts derive from CD23- activated B cells after the extinction of IL-4/STAT6 signaling and IRF4 induction
Plasmablasts derive from CD23- activated B cells after the extinction of IL-4/STAT6 signaling and IRF4 induction
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DOI：
10.1182/blood.2020005083
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发表时间：
2021-03-04
期刊：
影响因子：
20.3
通讯作者：
Fest, Thierry
中科院分区：
文献类型：
--
作者：
Pignarre, Amandine;Chatonnet, Fabrice;Fest, Thierry
B细胞终末分化为抗体分泌细胞（ASC）是适应性免疫应答的关键组成部分。然而，这是一个非常敏感的过程，功能障碍导致各种淋巴组织增生性肿瘤，包括生发中心来源的淋巴瘤。为了更好地表征驱动人类原代幼稚B细胞ASC分化的晚期基因组事件，我们使用了我们的体外分化系统以及RNA测序和转座酶可及染色质测定与高通量测序（ATAC测序）的组合。我们发现了两种驱动人类终末B细胞分化的机制。首先，在对白细胞介素-4（IL-4）的初始应答后，致力于ASC命运的细胞下调CD 23标记物和IL-4信号传导，而维持IL-4信号传导的细胞不分化。其次，人CD 23（-）细胞也将IRF 4蛋白增加到ASC分化所需的水平，但它们独立于先前在小鼠中描述的泛素介导的降解过程。最后，我们发现，CD 23（-）细胞携带其先前活化的B细胞状态的印记，是浆母细胞的前体，并具有与体内前浆母细胞相似的表型。总之，我们的研究结果提供了一个前所未有的基因组特征的命运之间的决定激活B细胞和浆母细胞，这提供了新的见解，推动淋巴瘤生物学的病理机制。
The terminal differentiation of B cells into antibody-secreting cells (ASCs) is a critical component of adaptive immune responses. However, it is a very sensitive process, and dysfunctions lead to a variety of lymphoproliferative neoplasias including germinal center-derived lymphomas. To better characterize the late genomic events that drive the ASC differentiation of human primary naive B cells, we used our in vitro differentiation system and a combination of RNA sequencing and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC sequencing). We discovered 2 mechanisms that drive human terminal B-cell differentiation. First, after an initial response to interleukin-4 (IL-4), cells that were committed to an ASC fate downregulated the CD23 marker and IL-4 signaling, whereas cells that maintained IL-4 signaling did not differentiate. Second, human CD23(-) cells also increased IRF4 protein to levels required for ASC differentiation, but they did that independently of the ubiquitin-mediated degradation process previously described in mice. Finally, we showed that CD23(-) cells carried the imprint of their previous activated B-cell status, were precursors of plasmablasts, and had a phenotype similar to that of in vivo preplasmablasts. Altogether, our results provide an unprecedented genomic characterization of the fate decision between activated B cells and plasmablasts, which provides new insights into the pathological mechanisms that drive lymphoma biology.