Epigenetic Regulation of Memory B Cell Differentiation and Reactivation

项目摘要 体液免疫依赖于B细胞分化为浆细胞，然后浆细胞分泌抗体。这些 抗体与抗原结合以促进微生物的中和和清除。自然感染和疫苗接种 诱导幼稚B细胞分化为浆细胞或记忆B细胞。记忆B细胞与浆细胞不同， 维持对抗原的反应性，并且可以通过随后的攻击来刺激，类似于幼稚B细胞。 然而，在第二次刺激时，记忆B细胞更快地分化为浆细胞，并产生更高的 亲和性更强的抗体类型转换。记忆B细胞可以是IgM+或同种型转换的。现在， IgM+记忆B细胞是再激活反应的关键参与者。IgM+记忆B细胞以一种 定量和定性的方式比幼稚B细胞更有效，类似于类别转换记忆B 细胞这表明记忆B细胞反应的差异不仅仅是由于类别转换的B细胞 受体。我们认为，记忆B细胞具有改变的染色质结构，这有助于它们的增强。 对后续感染的反应能力。这些变化可能是在启动子或增强子区域的关键 参与代谢和浆细胞分化的基因，如Pdhx和Xbp 1。我们 基因组学数据显示，浆细胞比幼稚和活化的B细胞依赖更多的氧化磷酸化。 由于记忆B细胞分化为浆细胞的速度更快，这表明记忆B细胞将能够 在刺激时比幼稚B细胞更有效地进行氧化磷酸化。我们还表明， 幼稚B细胞向浆细胞的分化与细胞分裂和发生的特定表观遗传变化相关联 在每一个分裂。我们不知道记忆B细胞是否遵循相同或相似的表观遗传模式。 这个建议的总体目标是确定有助于增强记忆再激活的遗传因素 B细胞。为了实现这一点，目标1将使用各种感染/接种方法来确定 生物化学和表观遗传程序，定义记忆B细胞的代谢。目标2将描述 幼稚、IgM+和类别转换记忆B细胞向浆细胞的分化程序， 了解记忆细胞分化为浆细胞所需的分裂次数，以及 二次激发期间的转录组变化。因此，拟议的工作将确定 代谢基因编程是由表观遗传变化介导的，并增强了我们对代谢基因编程的理解。 记忆B细胞对免疫攻击作出反应。

Project Summary Humoral immunity relies on B cells to differentiate into plasma cells, which then secrete antibodies. These antibodies bind to antigen to facilitate neutralization and clearance of microbes. Natural infection and vaccination induce differentiation of naïve B cells to plasma cells or to memory B cells. Memory B cells, unlike plasma cells, maintain responsiveness to antigen, and can be stimulated by subsequent challenge, similar to a naïve B cell. However, upon secondary stimulation, memory B cells differentiate faster to plasma cells and produce higher affinity, more class-switched antibody. Memory B cells can be IgM+ or isotype-switched. It is now appreciated that IgM+ memory B cells are key players in the reactivation response. IgM+ memory B cells respond in a quantitatively and qualitatively more efficient manner than naïve B cells, similar to class-switched memory B cells. This suggests that the differences in memory B cell responses are not simply due to class-switched B cell receptors. We propose that memory B cells have an altered chromatin architecture that facilitates their enhanced ability to respond to subsequent infection. These changes are likely in the promoter or enhancer regions of key genes involved in metabolism and plasma cell differentiation, such as Pdhx and Xbp1, respectively. Our genomics data shows that plasma cells rely on more oxidative phosphorylation than naïve and activated B cells. Because memory B cells differentiate to plasma cells faster, it suggests that memory B cells will be able to perform oxidative phosphorylation more effectively upon stimulation than naïve B cells. We have also shown that naive B cell differentiation to plasma cells is coupled to cell division and to specific epigenetic changes that occur during each division. We do not know whether memory B cells follow the same or similar epigenetic patterns. The overall goal of this proposal is to identify genetic factors that contribute to enhanced reactivation by memory B cells. To accomplish this, Aim 1 will use a variety of infection / inoculation methods to determine the biochemical and epigenetic programs that define metabolism of memory B cells. Aim 2 will characterize the differentiation programs of naïve, IgM+ and class-switched memory B cells to plasma cells by seeking to understand the number of divisions required for memory cell differentiation to a plasma cell and how the transcriptome changes during secondary challenge. Thus, the work proposed will define the changes in metabolic gene programming that are mediated by epigenetic changes and enhance our understanding of how memory B cells respond to immune challenge.