IL-21 and CD40L synergistically promote plasma cell differentiation through upregulation of Blimp-1 in human B cells.
IL-21 and CD40L synergistically promote plasma cell differentiation through upregulation of Blimp-1 in human B cells.
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DOI：
10.4049/jimmunol.1201678
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发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Ye BH
中科院分区：
文献类型：
--
作者：
Ding BB;Bi E;Chen H;Yu JJ;Ye BH
在经历IG体细胞超突变和抗原选择后，生殖中心（GC）B细胞终末分化为记忆细胞或浆细胞（PC）。已知CD 40 L和IL-21/STAT 3信号传导途径在该过程中起关键作用，但尚不清楚B细胞转录程序如何解释和整合这两种类型的T细胞衍生信号。在这项研究中，我们使用纯化的人扁桃体GC B细胞和GC B细胞样细胞系来表征STAT 3在GC相关PC分化中的作用。当原代GC B细胞在PC分化条件下培养时，通过AG 490抑制STAT 3阻止了GC中心细胞向前浆母细胞（pre-PB）的转变，表明STAT 3是PC发育起始所必需的。在GC B细胞样人B细胞系中，尽管IL-21单独可诱导低水平Blimp-1表达，但最大Blimp-1上调和最佳PC分化需要IL-21和CD 40 L两者。CD 40 L虽然作为单一药剂对Blimp-1没有影响，但大大增加了IL-21触发的Jak-STAT 3信号传导的幅度和持续时间。在人PRDM 1基因座中，CD 40 L处理通过从内含子3中共享的BCL 6/STAT 3位点去除BCL 6（Blimp-1表达的有效抑制剂）来增强STAT 3上调Blimp-1的能力。因此，IL-21和CD 40 L通过至少两种不同的机制协作以协同促进Blimp-1活化和PC分化。
After undergoing Ig somatic hypermutation and antigen selection, germinal center (GC) B cells terminally differentiate into either memory or plasma cells (PCs). It is known that the CD40L and IL-21/STAT3 signaling pathways play critical roles in this process, yet it is unclear how the B cell transcription program interprets and integrates these two types of T cell derived signals. In this study, we characterized the role of STAT3 in the GC-associated PC differentiation using purified human tonsillar GC B cells and a GC B cell-like cell line. When primary GC B cells were cultured under PC differentiation condition, STAT3 inhibition by AG490 prevented the transition from GC centrocytes to pre-plasmablast (pre-PB) suggesting that STAT3 is required for the initiation of PC development. In a GC B cell-like human B cell line, although IL-21 alone can induce low-level Blimp-1 expression, maximum Blimp-1 upregulation and optimal PC differentiation required both IL-21 and CD40L. CD40L, while having no effect on Blimp-1 as a single agent, greatly augmented the amplitude and duration of IL-21 triggered Jak-STAT3 signaling. In the human PRDM1 locus, CD40L treatment enhanced the ability of STAT3 to upregulate Blimp-1 by removing BCL6, a potent inhibitor of Blimp-1 expression, from a shared BCL6/STAT3 site in intron 3. Thus, IL-21 and CD40L collaborate through at least two distinct mechanisms to synergistically promote Blimp-1 activation and PC differentiation.
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