Tracking CD40 signaling during germinal center development
Tracking CD40 signaling during germinal center development
复制标题
DOI：
10.1182/blood-2003-12-4291
复制
发表时间：
2004-12-15
期刊：
影响因子：
20.3
通讯作者：
Dalla-Favera, R
中科院分区：
文献类型：
--
作者：
Basso, K;Klein, U;Dalla-Favera, R
大量证据表明，生发中心（GC）和记忆B细胞的形成需要通过CD40受体（CD40）的信号传导。然而，体内B细胞发育的哪些阶段会激活CD40通路尚未完全清楚。为了解决这个问题，我们在体外诱导人转化的生发中心B细胞中的CD40信号传导，并通过DNA微阵列分析确定了一个CD40基因表达特征。然后在正常B细胞的基因表达谱中研究了这一特征，发现它存在于生发中心前和生发中心后的B细胞（初始B细胞和记忆B细胞）中，但令人惊讶的是，不存在于生发中心B细胞中。这一发现通过在淋巴组织中证实得到了验证，即核因子 - κB（NF - κB）转录因子在CD40刺激时会转移到细胞核，但在大多数生发中心B细胞中却保留在细胞质中，这表明不存在CD40信号传导。然而，一部分中心细胞和上皮下的B细胞显示多个NF - κB亚基的核染色，这表明一部分初始B细胞和记忆B细胞可能受到CD40信号传导或其他激活NF - κB的信号的影响。总之，这些结果表明，生发中心的扩增在没有CD40信号传导的情况下发生，CD40信号传导可能仅在生发中心反应的初始和最终阶段起作用。
Substantial evidence indicates that signaling through the CD40 receptor (CD40) is required for germinal center (GC) and memory B-cell formation. However, it is not fully understood at which stages of B-cell development the CD40 pathway is activated in vivo. To address this question, we induced CD40 signaling in human transformed GC B cells in vitro and identified a CD40 gene expression signature by DNA microarray analysis. This signature was then investigated in the gene expression profiles of normal B cells and found in pre- and post-GC B cells (naive and memory) but, surprisingly, not in GC B cells. This finding was validated in lymphoid tissues by showing that the nuclear factor-kappaB (NF-kappaB) transcription factors, which translocate to the nucleus upon CD40 stimulation, are retained in the cytoplasm in most GC B cells, indicating the absence of CD40 signaling. Nevertheless, a subset of centrocytes and B cells in the subepithelium showed nuclear staining of multiple NF-kappaB subunits, suggesting that a fraction of naive and memory B cells may be subject to CD40 signaling or to other signals that activate NF-kappaB. Together, these results show that GC expansion occurs in the absence of CD40 signaling, which may act only in the initial and final stages of the GC reaction.